CN1506359A - Novel coumarin amide derivatives and its preparation method, its pharmaceutical composition and application - Google Patents

Abstract

The present invention relates to new coumarin and its amide derivatives, their preparation method, their pharmaceutical composition, and their use as medicine, especially as kidney protection, treatment of hypertension, cardiovascular and cerebrovascular diseases, type II diabetes, tumor , Precancerous lesions and the application of edema drugs.

Description

Novel coumarin amide derivatives and its preparation method, its pharmaceutical composition and application

The present invention relates to new coumarin and its amide derivatives, their preparation method, their pharmaceutical composition, and their use as medicine, especially as kidney protection, treatment of hypertension, cardiovascular and cerebrovascular diseases, type II diabetes, tumor , Precancerous lesions and the application of edema drugs.

In 1990, the Federal German Medical Research Institute published a monograph on Meliloti Herba, saying that coumarin compounds in some Chinese herbal medicines can treat edema, thrombophlebitis, lymphatic stasis and other diseases. Scheel et al. (Microbiol Toxins 847-66, 1972) reported that coumarin has antibacterial, antiviral and antitumor effects. Kovach et al. (Arzneim-Forsch/Drug Res 20 1630-33, 1970) demonstrated that coumarin increased blood flow and improved myocardial ischemia. Casley-Smith, (Vasomed 6 232-4, 1994), Gaaffney, (J Pathol 133:229-42, 1981), Piller, (Br J Exp Pathol 59:319-26, 1978) and Knight, (Clin Sci 77 : 69-76, 1989) proved that coumarin has endothelial protection and promotion of lymphatic circulation and so on. Nair et al., (Carcinogenesis 12(1):65-69, 1991) demonstrated the anticancer effect of coumarins. Ishizuka et al., (U.S. Patent No.5,096,924, demonstrated that substituted coumarins have anticancer effects. Marshall et al., (L.Biol.Resp.Mod.8:62, 1989), reported that coumarin enhanced immune function. As The mononuclear cells of cancer patients are significantly increased, thereby increasing the anticancer ability. Preuss-Ueberschar et al., (Drug Res.34: 1305, 1313, 1984), proved that coumarin is not teratogenic. Takagaki, Hidetsugu et al. proved that 3- , the effect of 4-, 7-hydroxyl or alkoxy substituted coumarin in the treatment of heart disease (EP 0796854 A1, 1997).Markal et al. proved that substituted 4-aryl coumarin can treat viral infections, especially herpes zoster, Herpes simplex etc. have better effect (WO 98/25608,1998). Reports such as Trkovnik 7-hydroxyl 4-methyl coumarin etc. can treat or prevent renal sclerosis, pancreatitis, bladder and digestive tract diseases (WO 99/ 21550,1999). Takagaki, Hideji etc. reported that coumarin derivatives have inhibitory effect on rat diabetes induced by streptozotocin (Jpn.Kokai Tokkyo Koho JP 07277972,1995). Scott et al. reported that 3-amide 4-hydroxycoumarin Compounds are effective (US 005723476A, 1998) to type II diabetes model. Han Xingmei et al. have reported that 6,7-dimethoxycoumarin is effective for acute renal failure induced by endotoxin (Chinese Pharmacology Bulletin, 1999, 15, 4:332-5). Len reported that TGF-β antagonists can be used to prevent chronic nephritis and other diseases (PCT Int.Appl.WO 2001019396A1)

In our research work, we synthesized a series of coumarin derivatives and studied the relevant biological activities; for example, Huang Xiaolong et al. proved that 3-acetyl and 3-ketoaldehyde substituted coumarins have better anti-skeletal Effects (Acta Pharmaceutica Sinica, 1996, 31, 6: 431-436; Acta Pharmacina Sinica, 1996, 31, 7: 509-516). The retinoid coumarin compounds studied by Xu Shiping have strong differentiation-inducing, anti-mutation and anti-carcinogenic effects (Chinese patent, application number: 97116602.1, publication number: CN1207392-volume 15, phase 6, 1999) . The 6- or 7-substituted styryl, 4-styryl and 4-, 6- or 7-substituted phenyliminomethine coumarin compounds studied by Xu Song et al. have anticancer activity (Acta Pharmacologica, 2000, 35, 2: 103-107; Acta Pharmaceutical Sinica, 2001, 36, 4: 269-273; Acta Pharmaceutical Sinica, 2002, 37, 2: 113-116).

In the continuation of the research on coumarin compounds, a series of new coumarin and its amide compounds were synthesized, and it was found that this type of coumarin amide compounds has a better effect on transforming growth factor-β1 (TGF-β1). Inhibition, the inhibition of coumarin on TGF-β, has not been reported in other literature so far. Substances that inhibit TGF-β are substances related to the treatment of chronic renal dysfunction, diabetic renal dysfunction, and the like. At the same time, it can also significantly reduce angiotensin II (AII), so the medicine of the present invention is relevant to the medicine research of chronic renal failure, nephritis, hypertension, even liver cirrhosis and pulmonary fibrosis. As reported by len, TGF-β antagonists can be used to prevent chronic nephritis and other diseases (PCT Int.Appl.WO 2001019396A1)

Renal insufficiency, especially chronic renal insufficiency, is the result of kidney damage and progressive deterioration caused by various etiologies. Among primary kidney diseases, chronic glomerulonephritis is common, followed by tubulointerstitial nephritis. Among secondary nephropathy, diabetic nephropathy is common. Among the current causes of chronic renal insufficiency, diabetic nephropathy accounts for 27% of the first, and it is still increasing day by day, hypertension accounts for 22.7%, and glomerulonephritis has dropped from the previous first to the third. Accounted for 21.2%, other causes accounted for 26.6%. Kidney disease is a common disease. No matter what the etiology is, whether it is immune mechanism or non-immune mechanism, if it is not treated effectively, it will cause chronic renal insufficiency and irreversible damage.

Studies have shown that transforming growth factor-β1 (transforming growth factor β1, TGF-β1) and renin-angiotensin system are closely related to renal insufficiency caused by various reasons. Four hours after partial nephrectomy in rats, TGF-β1 began to increase, which in turn affected the renin-angiotensin system. The continuous increase and overexpression of TGF-β1 inhibited matrix degradation, promoted matrix integration, and correlated with renal insufficiency Proportional to proteinuria and matrix fibrosis. Therefore, glomerulosclerosis and interstitial fibrosis are directly related to TGF-β1. Therefore, the renin-angiotensin system and TGF-β1 are the two most important factors related to renal insufficiency, and the inhibition of the former is closely related to the reduction of TGF-β1 production, suggesting that the increase of TGF-β1 may be the reason for the development of kidney damage. The important cause of late renal insufficiency is the target for finding an ideal anti-renal failure drug.

Coumarin has a wide range of biological activities, but no other reports have been seen in the treatment of chronic renal failure. The compound of the present invention is a new type, and has a very obvious effect of inhibiting TGF-β1. The increase of TGF-β1 is a sign of kidney damage. An important cause of the development of advanced renal failure. It has been verified that the compound of the present invention has a better effect on treating renal insufficiency. Renal insufficiency, especially chronic renal insufficiency, is a chronic disease that is difficult to treat. With the continuous increase of diseases such as diabetes and hypertension, its incidence rate is getting higher and higher. Good prevention method. The purpose of the present invention is exactly to develop the novel medicine of treating renal insufficiency.

In order to overcome the deficiencies in the prior art, the object of the present invention is to provide a new coumarin, especially its amide derivatives.

Another object of the present invention is to provide a preparation method of coumarin amide derivatives.

One aspect of the present invention relates to a pharmaceutical composition, which includes a compound of general formula (I), its isomer and a carrier commonly used in the field of pharmacy as an active ingredient.

Another object of the present invention is to provide a new coumarin amide derivative and its composition as an inhibitor of transforming growth factor-β1 and angiotensin II.

Another object of the present invention is to provide a kind of new coumarin amide derivatives and its composition in the preparation of treatment of kidney disease (such as various chronic nephritis, diabetic nephropathy and hypertensive renal damage), type II diabetes, heart disease Cerebrovascular, hypertension drug application.

Specifically, one aspect of the present invention relates to compounds represented by general formula (I)

in:

R _is selected from H, carboxyl, ester, 5'-(phenyloxadiazolyl-2'), 5'-(pyridyl-4"-oxadiazolyl-2'), CONHR ₉ ,

Wherein R ₉ is selected from C ₂ -C ₈ fatty acid, benzamido, isonicotinyl amino, unsubstituted, monosubstituted or multi-substituted phenyl, the substituent on the benzene ring can be OH, C ₁ -C ₈ alkane Oxygen, CF ₃ , Carboxyl, Ester, OCH ₂ CO ₂ H, NO ₂ , Halogen, SO ₃ H, SO ₂ NHR ₁₁ ,

Wherein R is selected from _amidino , 2"-thiazolyl, 3"-(5"-methylisoxazolyl), 2"-pyrimidinyl, 2"-(4", 6"-dimethylpyrimidinyl ), 4"-(5", 6"-dimethoxypyrimidinyl);

R ₄ is selected from H, CONHR ₁₀ , R ₁₀ is selected from C ₂ -C ₈ fatty acid, benzamido, isonicotinamide, unsubstituted, monosubstituted or polysubstituted phenyl, the substituent on the benzene ring can be OH, C ₁ -C ₈ alkoxy, CF ₃ , carboxyl, ester, OCH ₂ CO ₂ H, NO ₂ , halogen, SO ₃ H, SO ₂ NHR ₁₂ , where R ₁₂ is amidino, 2”-thiazole Base, 3"-(5"-methylisoxazolyl), 2"-pyrimidinyl, 2"-(4", 6"-dimethylpyrimidinyl), 4"-(5", 6"- Dimethoxypyrimidinyl);

R ₅ is selected from H, C ₁ -C ₄ alkyl;

R ₆ is selected from H, C ₁ -C ₁₂ alkyl, halogen, NO ₂ , CONHR ₁₃ , wherein R ₁₃ is selected from substituted phenyl;

R ₇ is selected from H, OH, C ₁ -C ₄ alkyl, alkoxy, alkoxy acid, OCH ₂ CONHR ₁₄ , wherein R ₁₄ is selected from unsubstituted, monosubstituted, polysubstituted phenyl, on the benzene ring Substituents can be OH, OCH ₃ , CF ₃ , CO ₂ H, CO ₂ C ₂ H ₅ , NO ₂ ;

R ₈ is selected from H, C ₁ -C ₄ alkyl, alkoxy, NO ₂ ;

CONHR，其中R为n-丁酸基，o-，m-，p-苯酚基，o-，m-，p-苯甲酸基，o-，m-，p-苯甲酸酯基，甲氧苯基，m-羧基亚甲氧苯基3’-水杨酸基，4’-水杨酸基，m-CF₃-苯基，3’-CF₃-4’-NO₂-苯基，2’-COOH-4’-I苯基，异烟酰氨基，苯甲酰氨基，4-氨磺酰苯基，4-胍磺酰苯基，4-(2’-噻唑氨磺酰)苯基，4-(5’-甲基异噁唑-3’-氨磺酰)苯基，4-嘧啶氨磺酰苯基，4-二甲基嘧啶氨磺酰苯基，4-(5”，6”-二甲氧基嘧啶)氨磺酰苯基等；For the purposes of the present invention, preferred compounds include but are not limited to: R ₃ is selected from H, COOH, CO ₂ C ₂ H ₅ , 5'-(phenyloxadiazolyl-2'), 5'-( Pyridyl-4"-oxadiazolyl-2'),

CONHR, where R is n-butyrate, o-, m-, p-phenol, o-, m-, p-benzoate, o-, m-, p-benzoate, methoxy Phenyl, m-carboxymethyleneoxyphenyl 3'-salicylate, 4'-salicylate, m-CF ₃ -phenyl, 3'-CF ₃ -4'-NO ₂ -phenyl, 2'-COOH-4'-Iphenyl, isonicotinamide, benzamido, 4-sulfamoylphenyl, 4-guanidinesulfonylphenyl, 4-(2'-thiazolesulfamoyl)benzene Base, 4-(5'-methylisoxazole-3'-sulfamoyl)phenyl, 4-pyrimidinesulfamoylphenyl, 4-dimethylpyrimidinesulfamoylphenyl, 4-(5" , 6"-dimethoxypyrimidine) sulfamoylphenyl, etc.;

R ₄ is selected from H, CONHR ₁₀ , R ₁₀ is selected from H, 4-COOH-phenyl, 4-CO ₂ C ₂ H ₅ -phenyl, 3-CF ₃ -phenyl; R ₅ is selected from H, CH ₃ ;

R ₆ is selected from H, C ₂ H ₅ , nC ₆ H ₁₃ , NO ₂ , NH ₂ , Cl, Br, CONHR ₁₃ , wherein R ₁₃ is selected from carboxyl and ester substituted phenyl;

R ₇ is selected from H, OH, CH ₃ , OCH ₃ , OCH ₂ CONHR ₁₄ , wherein R ₁₄ is phenyl, o-, m-, p-hydroxyphenyl, o-, m-, p-carboxyphenyl , 4'-ethoxycarbonylphenyl, 3'-ethoxycarbonylphenyl, 3'-trifluoromethylphenyl, 3'-trifluoromethyl4-nitrophenyl, 4'-methoxyphenyl , 4'-salicylic acid group, 3'-salicylic acid group;

R ₈ is selected from H, CH ₃ , OCH ₃ , NO ₂ ;

For the purpose of completing the present invention, preferred compounds include but are not limited to compounds shown in general formula (Ia):

Wherein R ₄ , R ₅ , R ₆ , R ₇ , R ₈ represent the same as represented in each case of general formula I;

R=(CH) _3COOH ,

For the purpose of completing the present invention, preferred compounds include but are not limited to compounds shown in general formula (Ib):

Wherein R ₄ , R ₅ , R ₆ , R ₇ , R ₈ represent the same as represented in each case of general formula I;

_R'2 is selected from H, OH, COOH, etc.;

_R'3 is selected from H, OH, COOH, CF ₃ , OCH ₂ COOH, etc.;

_R'4 is selected from H, OH, COOH, COOEt, I, NO ₂ , OCH ₃ , SO ₃ H, SO ₂ NH ₂ ,

SONH(C=NH)NH ₂ ,

wait

_R'5 , _R'6 for H

For the purpose of completing the present invention, preferred compounds include but are not limited to compounds as shown in the following table of the general formula: wherein R-R8 groups, except those marked, are all H; in the table, _R'2- R' ₆ groups, except those indicated, are all H.

In the present invention, the term "halogen" refers to fluorine, chlorine, bromine, iodine. The terms "lower alkyl" and "lower alkane" are linear or branched alkyl groups of 1 to 6 carbon atoms.

According to the present invention, the compound of the present invention may exist in the form of isomers, and generally speaking "the compound of the present invention" includes the isomers of the compound.

The compound of the present invention may have double bond cis-trans isomers, and the asymmetric center has S configuration or R configuration, and the present invention includes all possible stereoisomers and mixtures of two or more isomers. If cis/trans isomers exist, the present invention relates to cis and trans forms as well as mixtures of these forms, and if desired individual isomers can be isolated according to conventional methods or prepared by stereoselective synthesis.

According to the embodiment of the present invention, the compound of the present invention also includes its pharmaceutically acceptable salt, salt hydrate, ester or prodrug.

According to the present invention also relates to the method for preparing the compound of the present invention, carry out nitration or double nitration with various substituted 3-ester group or carboxylic acid coumarin compound, obtain part of the compound of the present invention, also be the intermediate of part of the compound of the present invention . With the acids of these intermediates, various substituted coumarins of 3-carboxy, various substituted coumarins of 4-carboxy, various substituted coumarins of 6-carboxy, or various substitutions of 7-carboxyalkoxy Coumarin is prepared by reacting with corresponding various substituted amino compounds. The amidation reaction is carried out under the conditions of suitable reactants, catalysts and suitable solvents. These reagents include phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, 1,3-dicyclohexylimine (DCC), dipyridine carbonate (2-DPC), 1,3 - Diisopropylcarbimide (DIPC), 1-(3-dimethylaminopropyl)-3-ethylcarbimide (EDCI) and the like. Wherein preferred reactant is phosphorus pentachloride, phosphorus trichloride and thionyl chloride, more preferably phosphorus pentachloride, thionyl chloride. The catalysts used in the preparation of the compounds of the present invention include tertiary amines, pyridine, 4-dimethylaminopyridine and 4-pyrrolidinylpyridine and the like. Among them, tertiary amines and pyridine are preferable. More preferred is pyridine. The reaction is carried out in a suitable solvent or the above-mentioned condensing agent, such as anhydrous aprotic solvent, dimethyl sulfoxide (DMSO), toluene, dichloromethane, 1,2-dichloroethane, ethylene glycol dimethyl ether , tetrahydrofuran and N,N-dimethylformamide (DMF), etc. Among them, toluene, DMSO and DMF are preferable, and toluene and DMF are more preferable. The reaction temperature is 10-110°C, preferably 20-90°C, more preferably 30-80°C, particularly preferably 50-70°C.

The following reaction equations IIa, IIb, IIc, IId, Iie, If specify

The present invention therefore also relates to pharmaceutical compositions comprising the compound according to the invention as active ingredient together with customary pharmaceutical excipients or adjuvants. Typically the pharmaceutical compositions of the invention contain 0.1-95% by weight of the compound of the invention.

Pharmaceutical compositions of compounds of the present invention can be prepared according to methods well known in the art. When used for this purpose, the compound of the present invention can be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants, if necessary, to prepare an appropriate administration form or dosage that can be used as human or veterinary medicine form.

The compound of the present invention or the pharmaceutical composition containing it can be administered in the form of unit dosage, and the route of administration can be enteral or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneal or rectal, etc.

The route of administration of the compound of the present invention or the pharmaceutical composition containing it may be injection. Injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection.

The dosage forms for administration may be liquid dosage forms or solid dosage forms. For example, the liquid dosage forms can be true solutions, colloids, particulate dosage forms, emulsion dosage forms, and suspension dosage forms. Other dosage forms such as tablets, capsules, drop pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injections, etc.

The compound of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

Various carriers known in the art can be widely used for tableting unit dosage forms. Examples of carriers are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid Aluminum, etc.; wetting agents and binders, such as water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, acacia mucilage, gelatin paste, sodium carboxymethylcellulose , shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrants, such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbate Sugar alcohol fatty acid esters, sodium lauryl sulfonate, methylcellulose, ethylcellulose, etc.; disintegration inhibitors, such as sucrose, tristearin, cocoa butter, hydrogenated oil, etc.; absorption enhancers , such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants, such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

For example, in order to form a dosage unit into a pellet, various carriers known in the art can be widely used. Examples of carriers are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc, etc.; binders such as acacia, tragacanth, Gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium dodecylsulfonate, methylcellulose, ethylcellulose, etc.

For example, to form a dosage unit into a capsule, the compound of the present invention as an active ingredient is mixed with the above-mentioned various carriers, and the mixture thus obtained is placed in a hard gelatin capsule or a soft capsule. The active ingredient compound of the present invention can also be made into microcapsules, suspended in an aqueous medium to form a suspension, and can also be packed into hard capsules or made into injections for application.

For example, the compound of the present invention is made into injection preparations, such as solutions, suspension solutions, emulsions, and freeze-dried powder injections. This preparation can be aqueous or non-aqueous, and can contain one and/or more drugs A pharmaceutically acceptable carrier, diluent, binder, lubricant, preservative, surfactant or dispersant. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1,3-propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, and the like. In addition, in order to prepare isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin can be added to the preparation for injection, and in addition, conventional solubilizers, buffers, pH regulators, etc. can also be added. These excipients are commonly used in the field

In addition, colorants, preservatives, fragrances, correctives, sweeteners or other materials can also be added to the pharmaceutical preparations, if necessary.

In order to achieve the purpose of medication and enhance the therapeutic effect, the medicine or pharmaceutical composition of the present invention can be administered by any known administration method.

The dosage of the compound pharmaceutical composition of the present invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight, personality and individual reaction of the patient or animal, the route of administration, the frequency of administration, Therapeutic purposes, and thus the therapeutic doses of the present invention, can vary widely. Generally speaking, the dosages of the pharmaceutical ingredients in the present invention are well known to those skilled in the art. According to the actual amount of drug contained in the final preparation of the compound composition of the present invention, appropriate adjustments can be made to achieve the requirement of its therapeutically effective dose, so as to achieve the preventive or therapeutic purpose of the present invention. The suitable dosage range of the compound of the present invention per day The dosage of the compound of the present invention is 0.001-150 mg/Kg body weight, preferably 0.1-100 mg/Kg body weight, more preferably 1-60 mg/Kg body weight, most preferably 2-30 mg/Kg weight. . The above-mentioned dosage may be administered in a single dosage form or divided into several, eg, two, three or four dosage forms, which are limited by the clinical experience of the administering physician and the dosage regimen including the use of other therapeutic means.

The total dosage required for each treatment may be divided into multiple doses or administered in a single dose. The compound or composition of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs and the dosage can be adjusted.

Use known in vivo and in vitro test methods to measure the activity and effect of the compound and/or composition of the present invention, such as TGF-β1 antagonism test, treatment of renal insufficiency, etc., these methods are well known. Recent studies have confirmed that TGF-β1 is one of the most critical factors leading to glomerulosclerosis and interstitial fibrosis in advanced renal failure. Pharmacological experiments show that the compound of the present invention has the effect of blocking transformation growth factor-β1 from binding to receptors and inhibiting the production of transformation growth factor-β1. Of the 33 compounds tested at a dose of 10 μg/ml, 11 compounds had more than 50% activity, 8 compounds had more than 60% activity, 7 compounds had more than 70% activity, and 5 compounds had more than 80% activity , more than 90% of the compounds have 4. For the growth inhibition of mink lung epithelial cells induced by TGF-β1, among the 5 compounds tested, the activities of three compounds exceeded 60%, two compounds exceeded 70%, and one compound exceeded 90%. Therefore, the compound of the present invention can be used for the treatment of chronic kidney disease, including: ① primary kidney disease, common chronic glomerulonephritis, interstitial nephritis, chronic pyelonephritis, etc.; ② secondary kidney disease, common diabetes Nephropathy, hypertensive nephropathy, lupus nephropathy, etc.; ③Congenital and obstructive diseases, such as polycystic kidney disease, posterior urethral valve disease, neurogenic bladder hyperplasia, benign prostatic hyperplasia, urinary calculi, etc.

Further tests showed that it has a very obvious inhibitory effect on angiotensin II (AII, P<0.01). Transforming growth factor-β1 and renin-angiotensin system are closely related to the above-mentioned multiple causes of renal insufficiency, and are the two most important factors in the progressive deterioration of renal disease, and the inhibition of angiotensin II is associated with the transformation of growth The reduction of factor-βl production is closely related. Angiotensin II plays an important role in the production of various hypertension. Therefore, the compound of the present invention can treat renal hypertension, diabetic hypertension and peripheral vascular disease hypertension caused by various factors, as well as cardiovascular and cerebrovascular diseases caused by the above reasons.

In vivo tests show that the effect of chronic renal failure caused by 5/6 nephrectomy in rats, compared with positive control drugs Benazepril and Losartan, proves that the compound of the present invention is reducing serum urea nitrogen (BUN), creatinine (Cre), inhibiting transforming growth factor -βl (TGF-β1) and angiotensin II (AII) are better than Benazepril, but comparable to Losartan (slightly better).

The effect on renal interstitial fibrosis caused by unilateral ureteral ligation in rats shows that the test compound 149 is better than Losartan in every biochemical index, and quite (slightly better) with Benazepril, but the pathological results show that the present invention's The compound is better than Benazepril and comparable to Losartan.

The test compound has very little toxicity. When the dose was 5g/Kg and 10g/Kg, it was continuously observed for two weeks, and no animal died, and no other abnormalities were seen in the mice, indicating that its toxicity is small and the safety factor is relatively large. In addition, the microbial reverse mutation test results of the tested compound 149 were all negative, indicating no mutagenic effect.

The following examples are used to further illustrate the present invention, but this does not imply any limitation to the present invention.

Example 1 Synthesis of 3-ethoxycarbonyl-6-chloro-7-hydroxyl-8-nitrocoumarin (241)

Add 2.75g (10.2mmol) of 3-ethoxycarbonyl-6-chloro-7-methoxycoumarin to 10ml of concentrated sulfuric acid, and add 1.74g (20.4mmol) of concentrated nitric acid in batches under cooling in an ice-salt bath. After chromatographic tracking until the reaction was complete, ice was added to terminate the reaction, filtered, washed with water, and dried to obtain 1.52 g of the title compound (241).

H-NMR 300MHz(DMSO): 1.266(t, 3H, _CH3 ); 4.232(q, 2H, _CH2 ); 8.017(s, 1H, 5-H); 8.593(s, 1H, 4-H)

Compounds 229-246 in Table 2 can be prepared according to this method

Example 2 Synthesis of 3-ethoxycarbonyl-6-ethyl-7-hydroxyl-8-nitrocoumarin (233)

According to the preparation method of Example Compound 241, the preparation of Compound 233 is different in that the nitration reaction is carried out with 3-ethoxycarbonyl-6-ethyl-7-methoxycoumarin to obtain Compound 233

H-NMR 300MHz (DMSO): 1.262 (t, 3H, 6-ethyl-CH ₃ ), 1.401 (t, 3H, ester-CH ₃ ), 2.753 (q, 2H, 6-ethyl-CH ₂ ) , 3.988 (s, 3H, 7-OCH ₃ ), 4.408 (q, 2H, ester-CH ₂ ), 7.527 (s, 1H, 5-H), 8.479 (s, 1H, 4-H)

Example 3 Synthesis of 3-ethoxycarbonyl-6-nitro-7,8-dimethoxycoumarin (227)

According to the preparation method of Example Compound 241, the preparation of Compound 229 is different in that the nitration reaction is carried out with 3-ethoxycarbonyl-7,8-dimethoxycoumarin to obtain Compound 229

H-NMR 300MHz (DMSO): 1.397 (t, 3H, ester-CH ₃ ), 4.063-4.118 (d, 6H, 7, 8-OCH ₃ ), 4.423 (q, 2H, ester-CH ₂ ), 7.757(s, 1H, 5-H), 9.252(s, 1H, 4-H)

Example 4 Synthesis of 3-ethoxycarbonyl-6,8-dinitro-7-methoxycoumarin (239)

According to the preparation method of Example Compound 241, the preparation of Compound 239 is different in that 3-ethoxycarbonyl-7-methoxycoumarin is used for double nitration reaction to obtain Compound 239

H-NMR 300MHz (DMSO): 1.290 (t, 3H, ester-CH ₃ ), 4.011 (s, 3H, 7-OCH ₃ ), 4.292 (q, 2H, ester-CH ₂ ), 8.873 (s, 1H, 4-H), 8.955(s, 1H, 5-H)

Example 5 Synthesis of 3-ethoxycarbonyl-6,8-dinitro-7-hydroxycoumarin (237)

According to the preparation method of Example Compound 241, the preparation of Compound 237 is different in that 3-ethoxycarbonyl-7-hydroxycoumarin is used for double nitration reaction to obtain Compound 237

H-NMR 300MHz (DMSO): 1.237 (t, 3H, ester-CH ₃ ), 4.196 (q, 2H, ester-CH ₂ ), 8.399 (s, 1H, 4-H), 8.636 (s, 1H, 5 -H)

Example 6 Synthesis of 3-(3'-hydroxyl-4'-carboxyaniline carbonyl)-6-ethyl-7-methoxycoumarin (26)

Heat 248mg (1mol) 3-carboxy-6-ethyl-7-methoxycoumarin and _2ml SOCl2 to complete the reaction, remove _SOCl2 , add 153mg (1mol) 4-aminosalicylic acid and 2ml pyridine , heated to complete the reaction, and the resulting product was purified with DMSO to obtain 140 mg of the title compound (26).

H-NMR 300MHz(DMSO): 1.142(t, 3H, CH ₃ ), 2.569(q, 2H, CH ₂ ), 3.906(s, 3H, 7-OCH ₃ ); 7.069(d, 1H, 6'-H ), 7.098(s, 1H, 8-H), 7.509(s, 1H, 2'-H), 7.758(d, 1H, 5-H), 8.856(s, 1H, 4-H), 10.848(s , 1H, CONH), 11.399 (s, 1H, OH)

Compounds 1-109 in Table 1, Compounds 204-206, 208, 209, 213, 214, 217, 218, 220, 222-228 Compounds 247-249 in Table 2 were prepared according to the above steps.

Example 7 Synthesis of 3-(3'-carboxy-4'hydroxyaniline carbonyl)-6-ethyl-7-methoxy coumarin (27)

According to the preparation method of Example Compound 26, the preparation of Compound 27 is different in that 5-aminosalicylic acid is used instead of 4-aminosalicylic acid for the reaction to obtain Compound 27

H-NMR500MHz (DMSO): 1.162 (t, 3H, ethyl-CH ₃ ), 2.602 (q, 2H, ethyl-CH ₂ ), 3.937 (s, 3H, 7-OCH ₃ ), 6.786 (d, 1H , 5'-H), 7.178(s, 1H, 6-H), 7.746(d, 1H, 6'-H), 7.770(s, 1H, 5-H), 8.239(s, 1H, 2'- H), 8.834(s, 1H, 4-H), 10.583(s, 1H, CONH)

Elemental analysis: C ₂₀ H ₁₇ NO ₇

Calculated value: C62.66, H4.47, N3.65

Measured value: C62.87, H4.49, N3.71

Example 8 Synthesis of 3-(m-carboxyaniline carbonyl)-7-methoxycoumarin (2)

According to the preparation method of Example Compound 26, the preparation of Compound 2 is different in that 3-carboxy 7-methoxycoumarin is reacted with m-aminobenzoic acid to obtain Compound 2

Elemental analysis: C ₁₈ H ₁₃ NO ₆ 1/2H ₂ O

Calculated value: C62.07, H4.05, N4.02

Measured value: C62.72, H3.74, N4.55

Example 9 Synthesis of 3-(3'-hydroxyl-4'-carboxyaniline carbonyl)-7-methoxycoumarin (7)

According to the preparation method of Example Compound 26, the preparation of Compound 7 is different in that 3-carboxy-7-methoxycoumarin is reacted with 4-aminosalicylic acid to obtain Compound 7

H-NMR 300MHz (DMSO): 3.91(s, 3H, 7-OCH ₃ ), 7.08(d, 1H, 6-H), 7.11(s, 1H, 6'-H), 7.53(s, 1H, 2 '-H), 7.77 (d, 1H, 5-H), 7.95 (d, 1H, 5'-H), 8.91 (s, 1H, 4-H), 10.83 (s, 1H, CONH), 11.40 ( br, 1H, OH)

Elemental analysis: C ₁₈ H ₁₃ NO ₇

Calculated value: C60.85, H3.69, N3.94

Measured value: C60.52, H3.59, N4.10

Example 10 Synthesis of 3-(3'-carboxy-4'-hydroxyaniline carbonyl)-7-methoxycoumarin (8)

According to the preparation method of Example Compound 26 and Compound 8, the difference lies in the reaction of 3-carboxy-7-methoxycoumarin and 5-aminosalicylic acid. Compound 8

H-NMR 300MHz(DMSO): 3.906(s, 3H, 7-OCH ₃ ), 6.964(d, 1H, 5'-H), 7.037(d, 1H, 6-H), 7.083(s, 1H, 8 -H), 7.745(d, 1H, 6'-H), 8.001(d, 1H, 5-H), 8.234(s, 1H, 2'-H), 8.877(s, 1H, 4-H), 10.547(s, 1H, CONH), 11.103(br, OH)

Elemental analysis: C ₁₈ H ₁₃ NO ₇

Calculated value: C60.85, H3.69, N3.94

Measured value: C60.50, H3.62, N3.64

Example 11 Synthesis of 3-[4'-(5"-methylisoxazole-3")-sulfamoyl-anilinecarbonyl]-7-methoxycoumarin (19)

According to the preparation method of Example Compound 26, the preparation of Compound 19 is different in that 3-carboxy-7-methoxycoumarin is reacted with sulfamethoxazole (SMZ). Compound 19

Elemental analysis: C ₂₁ H ₁₇ N ₃ O ₇ S·1/2H ₂ O

Calculated value: C54.31, H3.91, N9.05

Measured value: C54.56, H3.49, N8.90

Example 12 Synthesis of 3-(3'-carboxypropylaminocarbonyl)-7-methoxycoumarin (203)

According to the preparation method of Example Compound 26, Compound 203 was prepared with the difference that 3-carboxy-7-methoxycoumarin was reacted with γ-aminobutyric acid. Compound 203

H-NMR 300MHz (DMSO): 1.719(t, 2H, 3'-H), 2.235(t, 2H, 2'-H), 3.311(t, 2H, 4'-H), 3.861(s, 3H, 7-OCH ₃ ), 7.001(d, 1H, 6-H), 7.074(s, 1H, 8-H), 7.861(d, 1H, 5-H), 8.771(s, 1H, 4-H)

Elemental analysis: C ₁₅ H ₁₅ NO ₆

Calculated value: C59.01, H4.95, N4.59

Measured value: C59.05, H4.60, N4.73

Example 13 3-[4'-(5"-methylisoxazole-3")-sulfamoylanilide carbonyl]-7-methoxy-8-methylcoumarin (55)

According to the preparation method of Example Compound 26, the preparation of Compound 55 is different in that 3-carboxy-7-methoxy-8-methylcoumarin and sulfamethoxazole (SMZ) are used for the reaction. Compound 55

Elemental analysis: C ₂₂ H ₁₉ N ₃ O ₇ S

Calculated value: C56.28, H4.08, N8.95

Measured value: C56.61, H4.06, N9.01

Example 14 Synthesis of 3-(m-carboxymethyleneoxyaniline carbonyl)-7,8-dimethoxycoumarin (64)

According to the preparation method of Example Compound 26, the preparation of Compound 64 is different in that 3-carboxy-7,8-dimethoxycoumarin and m-carboxymethyleneoxyaniline are reacted to obtain Compound 64

H-NMR 300MHz(DMSO): 3.852(s, 3H, 8-OCH ₃ ), 3.951(s, 3H, 7-OCH ₃ ), 4.641((s, 2H, OCH ₂ ), 6.676(q, 1H, 5 '-H), 7.198-7.420(m, 3H, 4', 6', 6-H), 7.502(s, 1H, 2'-H), 7.751(d, 1H5-H), 8.853(s, 1H , 4-H), 10.584(s, 1H, CONH)

Elemental analysis: C ₂₀ H ₁₇ NO ₈

Calculated value: C60.15, H4.29, N3.51

Measured value: C60.41, H4.65, N3.75

Example 15 3-(4'-guanidinosulfonylaniline carbonyl)-7,8-dimethoxycoumarin (66)

According to the preparation method of Example Compound 26, the preparation of Compound 66 is different in that 3-carboxy-7,8-dimethoxycoumarin and sulfaguanidine (SG) are reacted to obtain Compound 66

Elemental analysis: C ₁₉ H ₁₈ N ₄ O ₇ S 2H ₂ O

Calculated values: C47.30, H4.56, N11.61

Measured value: C47.34, H4.08, N11.00

Example 16 Synthesis of 3-(3'-carboxy-4'-hydroxyaniline carbonyl)-7,8-dimethoxycoumarin (60)

According to the preparation method of Example Compound 26, the preparation of Compound 60 is different in that 3-carboxy-7,8-dimethoxycoumarin and 5-aminosalicylic acid are reacted to obtain Compound 60

H-NMR 300MHz (DMSO): 3.849-3.947 (d, 6H, 7, 8-bis-OCH ₃ ), 6.962 (d, 1H, 5'-H), 7.233 (d, 1H, 6-H), 7.727 -7.755(d, 2H, 5, 6'-H), 8.210(s, 1H2'-H), 8.813(s, 1H, 4-H), 10.495(s, 1H, CONH)

Elemental analysis: C ₁₉ H ₁₅ NO ₈ 1/4H ₂ O

Calculated value: C58.61, H4.01, N3.59

Measured value: C58.27, H3.86, N3.92

Example 17 Synthesis of 3-(benzohydrazide carbonyl)-5-methyl-7-methoxycoumarin (210)

According to the preparation method of Example Compound 26, the preparation of Compound 210 is different in that 3-carboxy-5-methyl-7-methoxycoumarin and benzohydrazide are reacted to obtain Compound 210

H-NMR 300MHz(DMSO): 2.482(s, 3H, 5-CH ₃ ), 3.888(s, 3H, 7-OCH ₃ ), 6.979(d, 2H, 6, 8-H), 7.477-7.583(q , 2H, 3', 5'-H), 7.500(t, 1H, 5'-H), 7.889(d, 2H, 2', 6'-H), 8.792(s, 1H, 4-H), 10.24(s, 1H, CONH), 10.868(s, 1H, CONH)

Example 18 Synthesis of 3-(isoniazidylcarbonyl)-5-methyl-7-methoxycoumarin (213)

According to the preparation method of Example Compound 26, the preparation of Compound 213 is different in that 3-carboxy-5-methyl-7-methoxycoumarin and isoniazid are reacted to obtain Compound 213

H-NMR 300MHz (DMSO): 2.553 (s, 3H, 5-CH ₃ ), 3.878 (s, 3H, 7OCH ₃ ), 6.979 (d, 2H, 6, 8-H), 7.935 (d, 2H, 3 ', 5'-H), 8.781 (s, 1H, 4-H), 10.545 (s, 1H, CONH), 11.362 (s, 1H, CONH)

Example 19 Synthesis of 3-(3'-carboxy-4'-hydroxyaniline carbonyl)-5-methyl-7-methoxycoumarin (74)

According to the preparation method of Example Compound 26, the preparation of Compound 74 is different in that 3-carboxy-5-methyl-7-methoxycoumarin and 5-aminosalicylic acid are reacted to obtain Compound 74

Elemental analysis: C ₁₉ H ₁₅ NO ₇

Calculated values: C61.79, H4.09, N3.79

Measured value: C61.57, H4.07, N3.81

Example 20 Synthesis of 3-(3'-hydroxyl-4'-carboxyaniline carbonyl)-6-Cl-7-methoxycoumarin (87)

According to the preparation method of Example Compound 26, the preparation of Compound 87 is different in that 3-carboxy-6-Cl-7-methoxycoumarin and 4-aminosalicylic acid are reacted to obtain Compound 87

H-NMR 300MHz (DMSO): 3.996(s, 3H7-OCH ₃ ), 7.114(d, 1H, 6'-H), 7.376(s, 1H, 8-H), 7.485(s, 1H, 2'- H), 7.768(d, 1H, 5'-H), 8.146(s, 1H, 5-H), 8.839(s, 1H, 4-H), 10.721(s, 1H, CONH)

Elemental analysis: C ₁₈ H ₁₂ ClNO ₇

Calculated value: C55.47, H3.11, N3.59

Measured value: C55.97, H3.13, N4.48

Example 21 Synthesis of 3-(3'-carboxy-4'-hydroxyaniline carbonyl)-6-Cl-7-methoxycoumarin (88)

According to the preparation method of Example Compound 26, the preparation of Compound 88 is different in that 3-carboxy-6-Cl-7-methoxycoumarin and 5-aminosalicylic acid are reacted to obtain Compound 88

H-NMR 300MHz(DMSO): 4.010(s, 3H, 7-OCH ₃ ), 6.968(d, 1H, 5'-H), 7.380(s, 1H, 8-H), 7.752(d, 1H, 6 '-H), 8.153(s, 1H, 5-H), 8.211(s, 1H, 2'-H), 8.817(s, 1H, 4-H), 10.475(s, 1H, CONH)

Elemental analysis: C ₁₈ H ₁₂ ClNO ₇

Calculated value: C55.47, H3.11, N3.59

Measured value: C55.60, H3.18, N4.1

Example 22 Synthesis of 3-(3'-hydroxyl-4'-carboxyaniline carbonyl)-6-Br-7-methoxycoumarin (96)

According to the preparation method of Example Compound 26, the preparation of Compound 96 is different in that 3-carboxy-6-Br-7-methoxycoumarin and 4-aminosalicylic acid are reacted to obtain Compound 96

H-NMR 300MHz(DMSO): 3.996(s, 3H, 7-OCH ₃ ), 7.118(d, 1H, 6'-H), 7.343(s, 1H, 8-H), 7.496(s, 1H, 2 '-H), 7.774(d, 1H, 5'-H), 8.306(s, 1H, 5-H), 8.846(s, 1H, 4-H), 10.722H(s, 1H, CONH)

Example 23 Synthesis of 3-(4'-guanidinosulfonylaniline carbonyl)-6-ethyl-7-methoxycoumarin (32)

According to the preparation method of Example Compound 26, the preparation of Compound 32 is different in that 3-carboxy-6-ethyl-7-methoxycoumarin and sulfaguanidine (SG) are reacted to obtain Compound 32

H-NMR 300MHz (DMSO): 1.148 (t, 3H, ethyl-CH ₃ ), 2.572 (q, 2H, ethyl-CH ₂ ), 3.896 (s, 3H, OCH ₃ ), 6.690 (br, 4H, Guanidino-H), 7.125(s, 1H, 8-H), 7.709(s, 1H5-H), 7.739(q, 4H, Ar-H), 8.827(s, 1H, 4-H), 10.841( s, 1H, CONH)

Elemental analysis: C ₂₀ H ₂₀ N ₄ O ₆ S 1/4H ₂ O

Calculated value: C53.55, H4.60, N12.48

Measured value: C53.49, H4.63, N12.40

Example 24 3-(4'-guanidinosulfonylaniline carbonyl)-6-Cl-7-methoxycoumarin (92)

According to the preparation method of Example Compound 26, the preparation of Compound 92 is different in that 3-carboxy-6-Cl-7-methoxycoumarin and sulfaguanidine (SG) are reacted to obtain Compound 92

H-NMR 300MHz(DMSO): 3.999(s, 3H, 7-OCH ₃ ), 7.407(s, 1H, 8-H), 7.776(q, 4H, Ar-H), 8.172(s, 1H, 5- H), 8.860(s, 1H, 4-H), 10.787(s, 1H, CONH)

Elemental analysis: C ₁₈ H ₁₅ ClN ₄ O ₆ S

Calculated: C47.95, H3.35, N12.43

Measured value: C47.54, H3.45, N12.15

Example 25 Synthesis of 3-(3'-hydroxyl-4'-carboxyaniline carbonyl)-7-methoxy-8-methylcoumarin (43)

According to the preparation method of Example Compound 26, the preparation of Compound 43 is different in that 3-carboxy-7-methoxy-8-methylcoumarin and 4-aminosalicylic acid are reacted to obtain Compound 43

H-NMR 300MHz(DMSO): 2.215(s, 3H, 8-CH ₃ ), 3.912(s, 3H, 7-OCH ₃ ), 7.081(d, 1H, 6'-H), 7.182(d, 1H, 6-H), 7.612(s, 1H, 2'-H), 7.747(d, 1H, 5-H), 7.872(d, 1H, 5'-H), 8.834(s, 1H, 4-H) , 10.813(s, 1H, CONH)

Elemental analysis: C ₁₉ H ₁₅ NO ₇ 1/2H ₂ O

Calculated value: C60.32, H4.26, N3.70

Measured value: C60.26, H4.03, N4.14

Example 26 Synthesis of 3-(3'-carboxy-4'-hydroxyaniline carbonyl)-7-methoxy-8-methylcoumarin (44)

According to the preparation method of Example Compound 26, the preparation of Compound 44 is different in that 3-carboxy-7-methoxy-8-methylcoumarin and 5-aminosalicylic acid are reacted to obtain Compound 44

H-NMR 300MHz(DMSO): 2.209(s, 3H, 8-CH ₃ ), 3.753(s, 3H, 7-OCH ₃ ), 6.959(d, 1H, 5'-H), 7.168(d, 1H, 6-H), 7.723(d, 1H, 6'-H), 7.848(d, 1H, 5-H), 8.197(s, 1H, 2'-H), 8.794(s, 1H, 4-H) , 10.504(s, 1H, CONH)

Elemental analysis: C ₁₉ H ₁₅ NO ₇ 1/2H ₂ O

Calculated value: C60.32, H4.26, N3.70

Measured value: C59.66, H3.92, N3.81

Example 27 3-(4'-methoxyaniline carbonyl)-6-nitro-7-hydroxyl-8-methylcoumarin (146)

Heat 160mg (0.604mmol) 3-carboxy-6-nitro-7-hydroxy-8-methyl coumarin and 2ml thionyl chloride to complete the reaction, remove excess thionyl chloride, add 74.3mg ( 0.604mmol) of p-aminoanisole, 1ml of pyridine and 1ml of DMF, heated to make the reaction complete, filtered, washed with water, dilute hydrochloric acid, water and ethanol, dried, and refined with glacial acetic acid to obtain 170mg of product (146)

H-NMR 300MHz(DMSO): 2.280(s, 3H, Ar-CH ₃ ); 3.740(s, 3H, OCH ₃ ); 6.941(d, 2H, 3', 5'-H); 7.621(d, 2H , 2', 6'-H); 8.673(s, 1H, 5-H); 8.897(s, 1H.4-H); 10.374(s, 1H, CONH)

Compounds No. 110-203 and No. 225-228 in Table 1 were prepared according to the above operation steps.

Example 28 3-(4'-guanidinosulfonylaniline carbonyl)-6-nitro-7-methoxy-8-methylcoumarin (169)

According to the preparation method of Example Compound 146, the preparation of Compound 169 is different in that sulfaguanidine (SG) and 3-carboxy-6-nitro-7-methoxy-8-methylcoumarin are reacted, Refined with DMF. Compound 169H-NMR 300MHz (DMSO): 2.382 (s, 3H, 8-CH ₃ ), 3.940 (s, 3H, 7-OCH ₃ ), 6.677 (br, 4H, guanidino-H), 7.790 (q, 4H, Ar-H), 8.593(s, 1H, 5-H), 8.903(s, 1H, 4-H), 10.707(s, 1H, CONH)

Elemental analysis: C ₁₉ H ₁₇ N ₅ O ₈ S·1/2H ₂ O

Calculated: C47.10, H3.75, N14.46

Measured value: C47.27, H3.73, N14.58

Example 29 3-(4'-carboxyaniline carbonyl)-6-nitro-7,8-dimethoxycoumarin (110)

According to the preparation method of Example Compound 146, Compound 110 was prepared with the difference that p-aminobenzoic acid and 3-carboxy-6-nitro-7,8-dimethoxycoumarin were reacted. Compound 110

H-NMR 300 MHz (DMSO): 3.99-4.06 (q, 6H, 7, 8-bis-OCH ₃ ), 7.82 (d, 2H, J=8.7, Ar-H), 7.9 (d, 2H, J=8.7 , Ar-H), 8.15(s, 1H, 5-H), 9.09(s, 4-H) 10.91(s, 1H, CONH)

Example 30 3-(3'-carboxyanilinecarbonyl)-6-nitro-7,8-dimethoxycoumarin (111)

According to the preparation method of Example Compound 146, Compound 111 was prepared with the difference that m-aminobenzoic acid and 3-carboxy-6-nitro-7,8-dimethoxycoumarin were used for the reaction. Compound 111

H-NMR 300MHz (DMSO): 3.97-4.05 (q, 6H, 7, 8-bis-OCH ₃ ), 7.49 (t, 1H, 5'-H), 7.67 (d, 1H, 6'-H), 7.76(d, 1H, 4'H), 7.93(s, 1H, 2'-H), 8.32(s, 1H, 5-H), 9.08(s, 1H, 4-H), 10.66(s, 1H , CONH)

Example 31 3-[4'-(5", 6 "-dimethoxypyrimidine-4")-sulfamoylaniline carbonyl]-6-nitro-7,8-dimethoxycoumarin ( 123)

According to the preparation method of Example Compound 146, the preparation of Compound 111 is different in that sulfonamide 5,6-dimethoxypyrimidine (SDM') and 3-carboxy-6-nitro-7,8-dimethyl Oxycoumarin reacts. Compound 123

H-NMR 300MHz (DMSO): 3.694 (s, 3H, pyrimidine-OCH ₃ ), 3.894 (s, 3H, 8-OCH ₃ ), 4.064 (s, 3H, 7-OCH ₃ ), 7.886-7.996 (q, 4H, Ar-H), 7.974(s, 1H, 2”-H), 8.109(s, 1H, 5-H), 9.092(s, 1H, 4-H), 10.791(s, 1H, CONH), 10.947 (br, 1H, _SO2NH )

Example 32 3-(3'-hydroxyl-4'-carboxyanilinecarbonyl)-6-nitro-7-hydroxyl-8-methylcoumarin (148)

According to the preparation method of Example Compound 146, the preparation of Compound 148 is different in that 4-aminosalicylic acid and 3-carboxy-6-nitro-7-hydroxyl-8-methylcoumarin are reacted,

Compound 148

H-NMR 300MHz(DMSO): 2.27(s, 3H, Ar-CH ₃ ), 7.11(dd, 1H, J=7.8Hz, 1.8Hz, 6'-H), 7.498(d, 1H, J=1.8Hz , 2'-H), 7.775(d, 1H, J=7.8, 5'-H), 8.65(s, 1H, 5-H), 8.892(s, 1H, 4-H), 10.69(s, 1H , CONH)

Example 33 3-(3'-carboxy-4'-hydroxyaniline carbonyl)-6-nitro-7-hydroxyl-8-methylcoumarin (149)

According to the preparation method of Example Compound 146, the preparation of Compound 149 is different in that 5-aminosalicylic acid and 3-carboxy-6-nitro-7-hydroxyl-8-methylcoumarin are reacted to obtain the compound 149

H-NMR 300MHz(DMSO): 2.268(s, 3H, Ar-H), 6.971(d, 1H, J=8.7Hz, 5'-H), 7.747(dd, 1H, J=8.7Hz, 2.7Hz, 6'-H), 8.208(d, 1H, J=2.7Hz, 2'-H), 8.658(s, 1H, 5-H), 8.867(s, 1H, 4-H), 10.403(s, 1H , CONH)

Example 34 3-[4'-(2"-pyrimidinesulfamoyl)anilinecarbonyl]-5methyl-6,8-dinitro-7-hydroxycoumarin (200)

According to the preparation method of Example Compound 146, the preparation of Compound 200 is different in that sulfadiazine (SD) and 3-carboxy-5methyl-6,8-dinitro-7-hydroxycoumarin are reacted, Compound 200

H-NMR 300MHz(DMSO): 2.291(s, 3H, 5-CH ₃ ), 7.025(t, 1H, 5"-H), 7.884(q, 4H, Ar-H), 8.483(d, 2H, 4 ", 6"-H), 8.640(s, 1H, 4-H), 10.705(s, 1H, CONH)

Example 35 3-(4'-sulfamoylaniline carbonyl)-5 methyl-6,8-dinitro-7-hydroxycoumarin (198)

According to the preparation method of Example Compound 146, the preparation of Compound 198 is different in that aminobenzenesulfonamide and 3-carboxy-5methyl-6,8-dinitro-7-hydroxycoumarin are reacted to obtain Compound 198

H-NMR 300MHz(DMSO): 2.254(s, 3H, 5-CH ₃ ), 7.240(br, 2H, NH ₂ ), 7.788(q, 4H, Ar-H), 8.666(s, 1H, 4-H ), 10.676(s, 1H, CONH)

Example 36 3-(2"-thiazolesulfamoylaniline carbonyl)-5 methyl-6,8-dinitro-7-hydroxycoumarin (201)

According to the preparation method of Example Compound 146, the preparation of Compound 201 is different in that sulfathiazole (ST) and 3-carboxy-5methyl-6,8-dinitro-7-hydroxycoumarin are reacted, Compound 201

H-NMR 300MHz (DMSO): 2.291(s, 3H, 5-CH ₃ ), 6.802(d, 1H, Thiazole-H), 7.225(d, 1H, Thiazole-H), 7.737(q, 4H, Ar- H), 8.651(s, 1H, 4-H), 10.667(s, 1H, CONH)

Example 37 3-(4'-guanidinosulfonylaniline carbonyl)-5 methyl-6,8-dinitro-7-hydroxycoumarin (199)

According to the preparation method of Example Compound 146, the preparation of Compound 199 is different in that sulfaguanidine (SG) and 3-carboxy-5methyl-6,8-dinitro-7-hydroxycoumarin are reacted, Compound 199

H-NMR 300MHz (DMSO): 2.293 (s, 3H, 5-CH ₃ ), 6.685 (br, 4H, guanidino-H), 7.746 (q, 4H, Ar-H), 8.657 (s, 1H, 4 -H), 10.647(s, 1H, CONH)

Example 38 3-(2'-phenyl-1',3',4'-oxadiazole-5')-7-methoxy-8-methylcoumarin (216)

295mg (0.84mmol) of 3-(benzohydrazinocarbonyl)-7-methoxy-8-methylcoumarin and 4.6ml of phosphorus oxychloride were reacted at 100°C for 5 hours, after gradually cooling, poured Pour into ice water, filter, wash with water, dry to obtain 290mg, after refining with DMF, obtain 160mg,

H-NMR 300MHz (DMSO): 2.252 (s, 3H, 8-CH ₃ ); 3.968 (s, 3H, 7-OCH ₃ ); 7.174 (d, 1H, 6-H); 7.634 (m, 3H, Ar '-H); 7.812(d, 1H, 5-H); 8.088(m, 2H, Ar'-H); 8.874(s, 1H, 4-H)

Compounds 207, 210-212, 215, 216, 219, and 221 in Table 2 were all prepared according to the above operation steps.

Example 39 3-(2'-phenyl-1',3',4'-oxadiazol-5'yl)-7-methoxycoumarin (206)

According to the preparation method of Example compound 216, the preparation of compound 206 is different in that 3-(benzohydrazide carbonyl)-7-methoxycoumarin is used instead of 3-(benzohydrazide carbonyl)- 7-methoxy-8-methylcoumarin was reacted to obtain compound 206

H-NMR 300MHz (DMSO): 3.929 (s, 3H, 7-OCH ₃ ), 7.021 (d, 1H, 6-H), 7.085 (s, 1H, 8-H), 7.599-7.668 (m, 3H, Ar-H), 7.871(d, 1H, 5-H), 8.095(m, 2H, Ar-H), 8.898(s, 1H, 4-H)

Elemental analysis: C ₁₈ H ₁₂ N ₂ O ₄

Calculated value: C67.49, H3.78, N8.75

Measured value: C67.57, H3.98, N8.41

Example 40 3-[2'-(pyridyl-4")-1',3',4'-oxadiazole-5']-6-hexyl-7-methoxycoumarin (221)

According to the preparation method of Example Compound 216, the preparation of Compound 221 is different in that 3-(isoniazidocarbonyl)-6-hexyl-7-methoxycoumarin is used instead of 3-(benzohydrazide carbonyl) -7-Methoxy-8-methylcoumarin was reacted to obtain compound 221

H-NMR 300MHz (DMSO): 0.869 (t, 3H, hexyl-CH ₃ ), 1.240 (br, 6H, hexyl-CH ₂ ), 1.574 (t, 2H, hexyl-CH ₂ ), 2.734 (t, 2H, Hexyl-CH ₂ ), 3.959 (s, 3H, 7-OCH ₃ ), 7.116 (s, 1H, 8-H), 7.699 (s, 1H, 5-H), 8.070 (br, 2H, pyridine-H) , 8.920 (br, 2H, pyridine-H), 8.921 (s, 1H, 4-H)

Elemental analysis: C ₂₃ H ₂₃ N ₃ O ₄ 3H ₂ O

Calculated value: C60.12, H6.36, N9.15

Measured value: C59.51, H5.51, N8.96

Example 41 4-Methyl-7-(4'-ethoxycarbonylanilinecarbonylmethyleneoxy)coumarin (255)

Heat 60 mg (0.256 mmol) of 4-methyl-7-carboxymethyleneoxy coumarin and 2 ml of thionyl chloride to complete the reaction and remove excess thionyl chloride, dissolve the residue in 5 ml of dichloromethane, add A solution of 44mg (0.267mmol) of p-aminobenzoic acid ethyl ester in 5ml of dichloromethane and 3ml of pyridine, stirred for half an hour to precipitate a solid, then continued to stir for 1 hour, filtered, washed with dichloromethane and dried 80mg,

H-NMR 300MHz (DMSO): 1.293 (t, 3H, ester methyl); 2.389 (s, 3H, 4-methyl); 4.269 (q, 2H, ester-CH ₂ ); 4.881 (s, 2H, OCH ₂ ); 6.219(s, 1H, 3-H); 7.018(d, 1H, 8-H); 7.056(d, 1H, 6-H); 7.712(d, 1H, 5-H); 7.760(d , 2H, 2', 6'-H); 7.919(d, 2H, 3', 5'-H); 10.479(s, 1H, CONH)

Elemental analysis: C ₂₁ H ₁₉ NO ₆

Calculated value: C66.13, H5.02, N3.67

Measured value: C66.26, H4.91, N3.81

Compounds No. 250-264 in Table 2 were prepared according to the above steps.

Embodiment 42 4-methyl-7-aniline carbonyl methyleneoxy coumarin (248)

According to the preparation method of Example Compound 255, the preparation of Compound 248 is different in that phenylamine is used instead of p-aminobenzoic acid ethyl ester to react to obtain Compound 248

H-NMR 300MHz(DMSO): 2.377(s, 3H, 4-CH ₃ ), 4.825(s, 2H, 7OCH ₂ ), 6.208(s, 1H, 3-H), 6.997(m, 3H, 4', 6, 8-H), 7.306 (t, 2H, 3', 5'-H), 7.593 (d, 2H, 2', 6'-H), 7.711 (d, 1H, 5-H), 10, 144(s, CONH)

Elemental analysis: C ₁₈ H ₁₅ NO ₄

Calculated values: C69.89, H4.89, N4.53

Measured value: C69.61, H4.891, N4.58

Example 43 4-methyl-7-(4'-carboxyaniline carbonyl methyleneoxy)-coumarin (252)

According to the preparation method of Example Compound 255, the preparation of Compound 252 is different in that p-aminobenzoic acid is used instead of p-aminobenzoic acid ethyl ester to react to obtain Compound 252

H-NMR 300MHz(DMSO): 2.404(s, 3H, 4-CH ₃ ), 4.899(s, 2H, 7-OCH ₂ ), 6.235(s, 1H, 3-H), 7.036(s, 1H8-H ), 7.073(d, 1H, 6-H), 7.713(d, 1H, 5-H), 7.739-7.924(q, 4H, Ar-H), 10.491(s, 1H, CONH)

Elemental analysis: C ₁₉ H ₁₅ NO ₆ 1/4H ₂ O

Calculated: C63.77, H4.37, N3.92

Measured value: C63.76, H4.28, N4.24

Example 44 4-methyl-7-(4'-hydroxyaniline carbonyl methyleneoxy) coumarin (249)

According to the preparation method of Example Compound 255, the preparation of Compound 249 is different in that p-aminophenol is used instead of p-aminobenzoic acid ethyl ester to react to obtain Compound 249

H-NMR 300MHz(DMSO): 2.084(s, 3H, 4-CH ₃ ), 4.781(s, 2H, 7-OCH ₂ ), 6.230(s, 1H, 3-H), 6.705-7.390(q, 4H , Ar-H), 7.014(s, 1H, 8-H), 7.060(d, 1H, 6-H), 7.723(d, 1H, 5-H), 9.905(s, 1H, CONH)

Elemental analysis: C ₁₈ H ₁₅ NO ₅

Calculated values: C66.45, H4.65, N4.31

Measured value: C66.14, H4.62, N4.32

Example 45 4-methyl-7-(3'-carboxy-4'-hydroxyaniline carbonyl methyleneoxy)-coumarin (261)

According to the preparation method of Example Compound 255, the preparation of Compound 261 is different in that 5-aminosalicylic acid is used instead of ethyl p-aminobenzoate for reaction to obtain Compound 261

H-NMR 300MHz(DMSO): 2.495(s, 3H, 4-CH ₃ ), 4.818(s, 2H, 7-OCH ₂ ), 6.233(s, 1H, 3-H), 6.940(d, 1H, 6 -H), 7.052(s, 1H, 8-H), 7.077(d, 1H, 5'-H), 7.705(d, 1H, 6'-H), 7.739(d, 1H, 5-H), 8.138 (s, 1H, 2'-H)

Elemental analysis: C ₁₉ H ₁₅ NO ₇

Calculated values: C61.79, H4.09, N3.79

Measured value: C61.49, H3.96, N3.86

Example 46 4-methyl-7-(3'-trifluoromethylaniline carbonyl methyleneoxy)-coumarin (257)

According to the preparation method of Example Compound 255, the preparation of Compound 257 is different in that 3-trifluoromethylaniline is used instead of ethyl p-aminobenzoate for reaction to obtain Compound 257

H-NMR 300MHz(DMSO): 2.389(s, 3H, 4-CH ₃ ), 4.872(s, 2H, 7-OCH ₂ ), 6.220(s, 1H, 3-H), 7.027-7.075(m, 2H , 6, 8-H), 7.429(d, 1H, 6'-H), 7.567(t, 1H, 5'-H), 7.719(d, 1H, 5-H), 7.857(d, 1H, 4 '-H), 8.096(s, 1H, 2'-H), 10.446(s, 1H, CONH)

Elemental analysis: C ₁₉ H ₁₄ F ₃ NO ₄

Calculated value: C60.48, H3.74, N3.71

Measured value: C60.17, H3.45, N3.79

Example 47 4-methyl-7-(3'-trifluoromethyl-4'-nitroanilinecarbonylmethyleneoxy)-coumarin (258)

According to the preparation method of Example Compound 255, the preparation of Compound 258 is different in that 3-trifluoromethyl-4-nitroaniline is used instead of ethyl p-aminobenzoate for reaction to obtain Compound 258

H-NMR 300MHz(DMSO): 2.409(s, 3H, 4-CH ₃ ), 4.955(s, 2H, 7-OCH ₂ ), 6.243(s, 1H, 3-H), 7.061(s, 1H, 8 -H), 7.086(d, 1H, 6-H), 7.734(d, 1H, 5'-H), 8.127(d, 1H, 6'-H), 8.215(d, 1H, 5-H), 8.331(s, 1H, 2'-H), 10.945(s, 1H, CONH)

Elemental analysis: C ₁₉ H ₁₃ F ₃ N ₂ O ₆ 1/2H ₂ O

Calculated value: C52.91, H3.27, N6.50

Measured value: C53.19, H3.05, N6.76

Example 48 4,8-Dimethyl-7-(3'-trifluoromethylaniline carbonyl methyleneoxy)coumarin (262)

According to the preparation method of Example Compound 255, the preparation of Compound 262 is different in that 3-trifluoromethylaniline and 4-methyl-7-carboxymethyleneoxy-8-methylcoumarin are used to react, Compound 262

H-NMR 300MHz (DMSO): 2.291 (s, 3H, 8-CH ₃ ), 2.392 (s, 3H, 4-CH ₃ ), 4.934 (s, 2H, 7-OCH ₂ ), 6.237 (s, 1H, 3-H), 7.002(d, 1H, 6-H), 7.440(d, 1H, 6'-H), 7.564(d, 1H, 5'-H), 7.603(d, 1H, 5-H) , 7.816(d, 1H, 4'-H), 8.103(s, 1H, 2'-H), 10.503(s, 1H, CONH)

Elemental analysis: C ₂₀ H ₁₆ F ₃ NO ₄

Calculated value: C61.38, H4.12, N3.58

Measured value: C61.16, H4.03, N3.67

Example 49 4,8-dimethyl-7-(3'-hydroxyl-4'-carboxyanilinecarbonylmethyleneoxy)coumarin (264)

According to the preparation method of Example Compound 255, the preparation of Compound 264 is different in that 4-aminosalicylic acid and 4-methyl-7-carboxymethyleneoxy-8-methylcoumarin are reacted to obtain the compound 264

H-NMR 300MHz(DMSO): 2.270(s, 3H, 8-CH ₃ ), 2.371(s, 3H, 4-CH ₃ ), 4.931(s, 2H, 7-OCH ₂ ), 6.215(s, 1H, 3-H), 6.958(d, 1H, 6-H), 7.087(d, 1H, 6'-H), 7.337(s, 1H, 2'-H), 7.546(d, 1H, 5'-H ), 7.717(d, 1H, 5-H), 10.455(s, 1H, CONH)

Elemental analysis: C ₂₀ H ₁₇ NO ₇

Calculated value: C62.66, H4.47, N3.65

Measured value: C62.43, H4.43, N3.88

Example 50 6-(4'-ethoxycarbonylanilinocarbonyl) coumarin (265)

Reflux 95mg (0.5mmol) of 6-carboxycoumarin and 210mg (1mmol) of phosphorus pentachloride in 50ml of toluene for 1 hour, after concentration, add 83mg (0.5mol) of ethyl p-aminobenzoate and 1ml of pyridine to continue to reflux After cooling for 10 minutes, it was acidified with hydrochloric acid to obtain a solid, and purified with ethanol to obtain 100 mg of the product (265).

H-NMR 300MHz (DMSO): 1.31(t, 3H, ester-CH ₃ ), 4.28(q, 2H, ester-CH ₂ ), 6.59(d, 1H, 3-H), 7.55(d, 1H , 8-H), 7.92(d, 2H, Ar'-H), 7.96(d, 2H, Ar'-H), 8.16(m, 2H, 4, 7-H), 8.34(d, 1H, 5 -H), 10.68(s, 1H, CONH)

Elemental analysis: C ₁₉ H ₁₅ NO ₅ 1/2H ₂ O

Calculated value: C65.80, H4.65, N4.04

Measured value: C66.07, H4.59, N4.06

Compound 266 was prepared according to this method.

Pharmacological experiment

Experimental example 1 The compounds of the present invention inhibit the proliferation of mink lung epithelial cells induced by TGF-β

Mink lung epithelial cells were inoculated into 24-well plates at a density of 3×10 ⁴ cells/well, and the culture conditions were 37° C., 5% CO ₂ , and MEM medium (containing 10% fetal bovine serum). The next day the medium was replaced with MEM containing 0.2% fetal bovine serum. After 24 hours, discard the medium, add fresh medium containing 10 pmol/L TGF-β1 and the test compound, and incubate for 24 hours. [ ³ H]thymidine was added 2 hours before the end of incubation. Media was discarded and cells were washed with PBS. Dissolve the cells with 0.5mol/L NaOH solution and measure their radioactivity. The inhibitory effect of the test compound on [ ³ H]thymidine incorporation may reflect its inhibitory effect on cell proliferation. (The results are listed in Table 3)

Table 3 The inhibitory effect of test compounds on the proliferation of mink lung epithelial cells induced by TGF-β

Example compound number (10μg/ml) 26 92 73 7 2

Inhibitory percentage of mink lung epithelial cell proliferation (%) 70.7 95.0 15.1 67.1 27.1

Experimental example 2 Antagonism of compounds of the present invention to TGF-β1 receptor binding test

The Balb/c 3T3 cells were inoculated into 24-well plates, and the culture conditions were 37° C., 5% CO ₂ , and DMEM medium (containing 10% fetal bovine serum). After culturing for 2-4 days, when the cells are close to confluence, replace the culture medium with binding buffer (50mmol/L HEPES containing NaCl, KCl, MgSO ₄ and CaCl ₂ ), add 50pmol/L [ ¹²⁵ I]TGF-β1 to stimulate Assay while adding the test compound. After 210-240 min of cell incubation, the medium was discarded and the cells were washed with ice-cold binding buffer. Non-specific binding of 10 nmol/LTGF-β1 was determined. Cells were lysed in Triton X-100 buffer and radioactivity was measured. (See Table 4 for the results)

Table 4. Antagonism of TGF-β1 receptor binding by compounds of the present invention

Example compound Inhibition IC ₅₀ Example compound Inhibition IC ₅₀

(10μg/ml) (%) (μg/ml) (10μg/ml) (%) (μg/ml)

1 32.2 42 4.1

2 74.1 13.8 49 15.5

3 11.7 55 52.3

6 -6.0 66 52.3

7 94.2 7.8 67 16.2

9 11.4 73 60.0

12 5.1 79 16.2

14 35.9 83 21.2

21 10.1 87 91.1

22 37.4 88 111.2 5.3

25 11.6 91 34.7

26 95.4 8.5 92 106.4

27 77.2 93 29.7

31 29.2 96 82.3

33 32.1 104 42.8

34 36.4 206 -0.7

37 41.4

Experimental example 3 The protective effect of the compound of the present invention on chronic renal failure caused by nephrectomy in 5/6 rats

The model of chronic renal failure induced by partial nephrectomy in rats was established according to the "Guiding Principles for Preclinical Research of New Drugs".

Male Wistar rats with a body weight of about 200 g were taken and injected intraperitoneally with pentobarbital sodium 35 mg/kg. After anesthesia, the right kidney was surgically removed, the upper and lower poles of the left kidney were removed, the bleeding was stopped, the abdominal cavity was closed, and sutured. Four weeks after the operation, serum urea nitrogen, creatinine, and urine protein were detected, the level of angiotensin II (AII) was determined by radioimmunoassay, and the level of TGF-β1 was determined by ELISA. Randomize the group and start dosing. Every group of 30 mice, assuming sham operation group, model control group, Benazepril (4mg/kg) and Losartan (10mg/kg) positive control drug group, test drug (embodiment 149) 7.5mg/kg, 15mg/kg and 30m/kg three dose groups. All were administered by intragastric administration, once a day, 6 times a week, until 16 weeks after the operation. Weigh the body weight every week, and observe the growth status of the rats; at postoperative 8 weeks (administration for 4 weeks), postoperative 12 weeks (administration for 8 weeks), postoperative 16 weeks (administration for 12 weeks), each group was measured respectively Indicators, some animals were sacrificed, and kidneys were taken for pathology.

The renal pathological damage of the chronic renal failure model in rats is mainly glomerulosclerosis and interstitial fibrosis. The glomerular sclerosis is divided into five grades (0-IV) according to the degree. The glomeruli were completely sclerotic and hyalinized. Fifty glomeruli were continuously observed in slices of each animal in each group, and the percentages of glomeruli lesions in each group were calculated according to five grades.

Four weeks after the establishment of the model, serum BUN increased by 111.21% (p<0.01), urine protein increased by 86.13% (p<0.01), and TGF-β1 level increased by 70.48% (p<0,02), indicating that the model was established successfully.

Model establishment 12 weeks (administration 8 weeks) pathology result shows, embodiment 149 compound 30mg/kg dosage group and Losartan group retain more glomeruli above grade 0 than model group, there is significant difference, (p＜0.05), The glomerular lesion score was significantly lower than that of the model group. Some animals in the Benazpril group had more serious infiltration of inflammatory cells, most of the tubules were severely dilated, and protein-like substances were precipitated.

Model establishment 16 weeks (administration 12 weeks) pathology result shows, test compound (149) 30mg/kg dosage group, III grade lesion globule is obviously less than model group (p＜0.01), positive drug Losartan is also smaller than matched group ( p<0.05). The positive drug Benazepril group had the highest glomerular lesion score, moderate to severe renal interstitial inflammatory cell infiltration, fibrous tissue hyperplasia, severe tubule dilation, and protein-like substance precipitation in most cases.

The main data of the test results are listed in Table 5A-E.

Table 5. The compound of the present invention is to the protective effect of chronic renal failure caused by nephrectomy in 5/6 rats

A. Changes in serum creatinine (Scr.) and blood urea nitrogen (BUN) after 8 weeks of administration (12 weeks after operation)

Dosage

Group (mg/k Scr.(mg/dL) Rate of Change (%) BUN(mg/dL) Rate of Change (%)

g)

Control group - 2.08±0.742 13.00±2.328

Model Group - 3.06±0.768 47.93↑ 29.37±3.079 ^# 125.90↑

Benazepril 4 3.54±1.140 15.36↑ 37.66±8.895 12.68↑

Losartan 10 2.34±0.268 ^* 23.46↓ 25.64±5.116 28.23↓

Compound 22.35 ±

7.5 2.14±0.500 ^* 30.26↓ 23.89↓

149 3.120 ^*

compound

15 1.80±0.550 ^* 41.34↓ 26.04±4.234 11.33↓

149

compound

30 1.89±0.184 38.20↓ 30.54 ± 3.98↑

149 11.697

^* : P<0.05, compared with the model group; #: P<0.05, compared with the control group; ↑: means increase; ↓: means decrease

B. Changes of serum TGF-β1, angiotensin II (AII) and urine protein (UP) after 8 weeks of administration (12 weeks after operation)

Dose TGF-β ₁ (ng/ml) AII(pg/ml) UP(mg/day)

Group (mg/ rate of change (%) rate of change (%) rate of change (%)

kg)

Control group - 20.1±6.2 154.5±22.7 18.3±2.5

                                                    

Model group - 25.6±12.1 27.4↑ 94.5±7.4 40.7±14.2 ^#

Benazepri ↑

4 40.9±26.6 59.8↑ 74.3±13.2 ^* 21.4↓ 51.1±23.6 25.8↑

l

Losartan 10 18.7±9.2 26.8↓ 96.7±32.1 2.2↑ 32.7±10.3 19.6↓

compound

7.5 20.0±6.7 21.8↓ 63.9±13.2 ^* 32.4↓ 30.1±16.6 26.0↓

149

compound

15 18.6±12.2 27.6↓ 49.9±21.3 ^* 47.2↓ 30.4±16.2 25.3↓

149

compound

30 18.9±10.1 26.1↓ 41.0±12.5 ^* 56.6↓ 34.3±12.1 15.7↓

149

^* : P<0.05, compared with the model group; #: P<0.05, compared with the control group;

↑: means increase; ↓: means decrease.

C. Changes in serum creatinine (Scr.) and blood urea nitrogen (BUN) 12 weeks after administration (16 weeks after operation)

Dose Scr.(mg/dL) BUN(mg/dL)

group

(mg/kg) Rate of change (%) Rate of change (%)

Control group - 2.25±0.39 21.24±3.354

...

Model group - 2.71±0.49 ^# 20.7↑ 83.32↑

8.755 ^#

Benazepril 4 2.28±0.70 19.01↓ 39.48±7.109 1.41↑

Losartan 10 2.21±0.48 ^* 22.73↓ 37.84±5.672 2.80↓

compound

7.5 2.73±0.78 0.75↑ 39.42±4.686 1.25↑

149

compound

                                                                                                 

149

compound

30 2.10±0.71 ^* 28.82↓ 36.60±5.422 5.99↓

149

^* : P<0.05, compared with the model group; #: P<0.05, compared with the control group; ↑: means increase; ↓: means decrease

D. Changes of serum TGF-β1, angiotensin II (AII) and urine protein (UP) after 12 weeks of administration (16 weeks after operation)

Dose TGF-β ₁ (ng/ml) AII(pg/ml) UP(mg/day)

Group (mg/kg) Rate of Change (%) Rate of Change (%) Rate of Change (%)

               

...

Control group - 18.2±8.9 130.0±37.6

...

...

Model group - 12.8±7.9 61.7±24.3

26.1 ^# ↑

Benazepri 4 12.8 ± 0.57↑ 47.8±12.0 22.6↓ 66.3 ± 22.3↑

l 14.8 31.9

                                                          ...

Losartan 10 7.48↓ 38.9±17.4 ^* 37.2↓ 18.4↓

...

Compounds 66.7 ±

7.5 13.6±7.1 6.28↑ 48.3±48.5 21.6↓ 23.1↑

149 38.8

Compounds 52.3 ±

15 12.3±7.7 3.91↓ 41.3±28.4 33.0↓ 0.06↓

149 34.4

Compounds 48.2 ±

30 11.6±6.7 9.38↓ 19.2±9.19 ^* 68.6↓ 11.1↓

149 31.6

^* : P<0.05, compared with the model group; #: P<0.05, compared with the control group; ↑: means increase; ↓: means decrease

E. Pathological results

Drug Administration Grading of Glomerulosclerosis

After Groups Level 0 Level I Level II Level III Level IV Level Total Score

week number

8 weeks Model group 10.0±17.3 38.7±21.2 31.5±17.3 13.6±18.3 1.8±3.3 4.9±1.5

Benazepril 12.2±19.0 29.6±23.9 28.1±18.1 19.6±24.4 5.9±11.2 5.5±2.6

Losartan 54.4±29.2 ^* 31.9±20.0 13.7±14.0 1.1±3.3 ^** 0 2.8±1.0 ^**

^*

Compound (149) 28.3±20.8 34.2±23.0 7.5±8.8 ^* 17.5±30.7 6.7±13.4 4.9±3.5

                                                   

Compound 149 37.5±29.3 ^* 27.5±16.3 18.8±9.9 13.3±20.7 2.9±8.2 3.9±1.7 ^*

  15mg/kg group

Compound 149 15.7±19.0 24.0±21.1 30.0±20.8 23.3±28.5 8.0±13.0 5.7±2.9

30mg/kg group

                                                                                 

12 weeks Model Group 1

0 0 19.1±27.1 46.2±15.6 34.8＝29.9.8±1.4

Benazepril 9

Losartan 0 10.0±2.9 45.7±17.7 41.9±25.6 2.8＝4.8 7.2±1.3 ^*

Compound 149 0 2.0±4.5 71.3±11.5 ^* 26.7±7.8 ^** 0 6.7±0.2 ^**

7.5mg/kg group ^*

Compound 149 0 8.1±14.1 38.1±27.4 46.2±26.1 9.1±12.6 7.7±1.7

  15mg/kg group

Compound 149 0 2.3±6.3 37.1±16.0 51.4±8.6 13.8＝20. 8.6±1.9

30mg/kg group 6

^* : P<0.05, compared with the model group

The above results show that the test compound (149) is better than Benazepril in every biochemical index, and comparable (slightly better) to Losartan. In addition, the pathological results showed that the test compound had no obvious effect on major organs such as heart, liver, spleen and lung in each dose group after three months of administration.

Experimental example 4 Inhibitory effect of the compound of the present invention on renal interstitial fibrosis caused by unilateral ureteral ligation in rats

Male Wistar rats, weighing 180-230 g, were injected intraperitoneally with pentobarbital sodium 35 mg/kg. After anesthesia, an incision was made on the left side of the lower abdomen, and the left ureter was ligated near the bladder. Suppose sham operation group, model control group, Benazepril (4mg/kg) and Losartan (10mg/kg) positive control drug group, test drug (embodiment 149) 5mg/kg, 10mg/kg and 20mg/kg three dosage groups . Two days before the operation, intragastric administration was started, once a day, 6 times a week, and the administration continued until 2 weeks after the operation. 14 days after operation (16 days after administration), creatinine and blood urea nitrogen were measured, and the results are listed in Table 6. In the model group, serum urea nitrogen (BUN) increased by 78.70% (p<0.01) and creatinine (Scr.) increased by 20.73% (p<0.05) on day 9 after operation, indicating that the model was established successfully.

Table 6 The inhibitory effect of compounds of the present invention on renal interstitial fibrosis caused by unilateral ureteral ligation in rats

Dosage

Group (mg/k Scr.(mg/dL) Change rate (%) BUN(mg/dL) Change rate (%)

g)

Control group - 1.45±0.44 16.23±2.70

Model Group - 2.20±0.14 ^# 51.58↑ 27.54±3.32 ^# 69.73↑

20.99 ±

Benazepril 4 1.92±0.29 12.50↓ 23.78↓

1.58 ^*

Losartan 10 2.15±0.51 2.31↓ 23.88±2.94 13.30↓

Compound 149 7.5 1.58±0.49 ^* 28.24↓ 23.71±4.17 13.92↓

...

Compound 149 15 1.61±0.36 ^* 26.50↓ 24.61↓

1.56 ^*

...

Compound 149 30 1.60±0.14 ^* 27.27↓ 24.58↓

2.04 ^*

^* : P<0.05, compared with the model group; #: P<0.05, compared with the control group; ↑: means increase; ↓: means decrease

In this test, the test compound 149 was better than Losartan in every biochemical index, but comparable (slightly better) to Benazepril. However, the pathological results were different. The infiltration of inflammatory cells was more obvious in the Benazepril group. Small abscesses formed in the renal medulla of 4/7 animals, and a large number of necrotic cells, inflammatory cells and pus cells accumulated. In the Losartan group, interstitial inflammatory cell infiltration and fibrous hyperplasia were significantly reduced, and small balloon thickening was not obvious. The interstitial inflammatory cell infiltration and fibrous proliferation in the administration group, especially in the high-dose group, were significantly reduced, and the glomerulus lesions were relatively mild. Therefore, in terms of pathology, it is better than Benazepril and comparable to Losartan.

Experimental example 5 The preliminary acute toxicity test of the compound of the present invention to mice

Two doses of test compound (149) 5g/kg and 10g/kg were given to mice by intragastric administration, no abnormality was found in the mice, and the body weight was weighed 48 hours after the administration, and the body weight of mice with 5g/kg and 10g/kg had no change. 14 days after the administration, the average body weight of the 5g/kg mice increased by 7g; the body weight of the 10g/kg mice increased by 5g, and no abnormalities were found in the rest, and no animal death occurred.

Experimental Example 6 The microbial reverse mutation test (Ames test) of the compound of the present invention

Histidine-deficient Salmonella typhimurium TA97, TA98, TA100, TA102 strains were used. The drug concentration is 0.5, 5, 50, 500, 5000 μg/dish. S9 is the microsomal fraction of rat liver homogenate induced by phenobarbital with a body weight of 200 g. The test compound (149) was tested in parallel with or without S9.

Referring to the Ames (1983) revision of the Salmonella typhimurium mammalian microsomal enzyme mutagenesis test method, the test compound (149) was subjected to plate incorporation detection of metabolic activation and non-metabolic activation. Inoculate the qualified liquid nitrogen preservation bacteria solution into the culture medium, and shake and culture at 37°C for 15 hours. Take 0.1ml of the above bacterial solution, add 100μl of test drug solution of different concentrations, add S9 mixed solution or 0.5ml of phosphate buffer solution, and incubate in a water bath at 37°C for 20 minutes. Then add 2ml of top agar and mix well and pour it into the plate covered with bottom agar. After culturing at 37°C for 48 hours, count the number of colonies in each plate.

The test compound (149) did not induce an increase in the number of reversion mutant colonies of each bacterial strain under this test dose, indicating that the Ames test result of the test compound was negative and had no mutagenic effect.

Claims (17)

1, a kind of compound as shown in general formula (I) It is characterized in that, R _is selected from H, carboxyl, ester, 5'-(phenyloxadiazolyl-2'), 5'-(pyridyl-4"-oxadiazolyl-2'), CONHR ₉ , Wherein R ₉ is selected from C ₂ -C ₈ fatty acid, benzamido, isonicotinyl amino, unsubstituted, monosubstituted or multi-substituted phenyl, the substituent on the benzene ring can be OH, C ₁ -C ₈ alkane Oxygen, CF ₃ , Carboxyl, Ester, OCH ₂ CO ₂ H, NO ₂ , Halogen, SO ₃ H, SO ₂ NHR ₁₁ , Wherein R is selected from _amidino , 2"-thiazolyl, 3"-(5"-methylisoxazolyl), 2"-pyrimidinyl, 2"-(4", 6"-dimethylpyrimidinyl ), 4"-(5", 6"-dimethoxypyrimidinyl); R ₄ is selected from H, CONHR ₁₀ , R ₁₀ is selected from C ₂ -C ₈ fatty acid, benzamido, isonicotinamide, unsubstituted, monosubstituted or polysubstituted phenyl, the substituent on the benzene ring can be OH, C ₁ -C ₈ alkoxy, CF ₃ , carboxyl, ester, OCH ₂ CO ₂ H, NO ₂ , halogen, SO ₃ H, SO ₂ NHR ₁₂ , where R ₁₂ is amidino, 2”-thiazole Base, 3"-(5"-methylisoxazolyl), 2"-pyrimidinyl, 2"-(4", 6"-dimethylpyrimidinyl), 4"-(5", 6"- Dimethoxypyrimidinyl); R ₅ is selected from H, C ₁ -C ₄ alkyl; R ₆ is selected from H, C ₁ -C ₁₂ alkyl, halogen, NO ₂ , CONHR ₁₃ , wherein R ₁₃ is selected from substituted phenyl; R ₇ is selected from H, OH, C ₁ -C ₄ alkyl, alkoxy, alkoxy acid, OCH ₂ CONHR ₁₄ wherein R ₁₄ is unsubstituted, mono-substituted, multi-substituted phenyl, a substituent on the benzene ring It can be OH.OCH ₃ , CF ₃ , CO ₂ H, CO ₂ C ₂ H ₅ , NO ₂ ; R ₈ is selected from H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, NO ₂ ; 2. The compound according to claim 1, characterized in that, R ₃ is selected from H, COOH, CO ₂ C ₂ H ₅ , 5'-(phenyloxadiazolyl-2'), 5'-(pyridyl-4"-oxadiazolyl-2'),

CONHR ₉ , where R ₉ is n-butyrate, o-, m-, p-phenol, o-, m-, p-benzoate, o-, m-, p-benzoate, Methoxyphenyl, 3'-salicylate, 4'-salicylate, m-CF ₃ -phenyl, 3'-CF ₃ -4'-NO ₂ -phenyl, 2'-COOH-4 '-I phenyl, isonicotinamide, benzamido, 3'-carboxymethyleneoxyphenyl, 4-sulfamoylphenyl, 4-guanidinesulfonylphenyl, 4-(2'-thiazole Sulfamoyl)phenyl, 4-(5'-methylisoxazole-3'-sulfamoyl)phenyl, 4-pyrimidinesulfamoylphenyl, 4-dimethylpyrimidinesulfamoylphenyl, 4-(5",6"-dimethoxypyrimidine)sulfamoylphenyl; R ₄ is selected from H, CONHR ₁₀ , R ₁₀ is H, 4-COOH-phenyl, 4-CO ₂ C ₂ H ₅ -phenyl, 3-CF ₃ -phenyl; R ₅ is selected from H, CH ₃ ; R ₆ is selected from H, C ₂ H ₅ , nC ₆ H ₁₃ , NO ₂ , NH ₂ , Cl, Br, CONHR ₁₃ , wherein R ₁₃ is 4-benzoic acid and 4-ethyl benzoate; R ₇ is selected from H, OH, CH ₃ , OCH ₃ , OCH ₂ CONHR ₁₄ , wherein R ₁₄ is phenyl, o-, m-, p-hydroxyphenyl, o-, m-, p-carboxyphenyl , 4'-ethoxycarbonylphenyl, 3'-ethoxycarbonylphenyl, 3'-trifluoromethylphenyl, 3'-trifluoromethylphenyl, 4'-methoxyphenyl, 4'- Salicylic acid group, 3'-salicylic acid group; R ₈ is selected from H, CH ₃ , OCH ₃ , NO ₂ ; 3. The compound according to claim 1, characterized in that, as shown in general formula (Ia)

Wherein, the definitions of R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ are the same as those in claim 1, R=(CH) _3COOH ,

4. The compound according to claim 1, characterized in that, as shown in general formula (Ib)

The definitions of R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ are the same as those in claim 1; _R'2 is selected from H, OH, COOH; _R'3 is selected from H, OH, COOH, CF ₃ , OCH ₂ COOH; _R'4 is selected from H, OH, COOH, COOEt, I, NO ₂ , OCH ₃ , SO ₃ H, SO ₂ NH ₂ , SONH(C=NH)NH ₂ ,

R' ₅ , R' ₆ is H. 5. The compound according to claim 2, characterized in that said compound is selected from one of the following groups of compounds, wherein, R ₃ =p-COOH-anilinecarbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =m-COOH-aniline carbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =o-COOH-aniline carbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =o-OH-anilinecarbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =m-OH-anilinecarbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =p-OH-anilinecarbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =m-OH-p-COOH-aniline carbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =m-COOH-p-OH-aniline carbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =o-COOH-pI-anilinecarbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =4-ethoxycarbonylaniline carbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =m-CF ₃ -anilinocarbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =m-CF ₃ -4-NO ₂ -anilinocarbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =4-sulfamoylaniline carbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =4-guanidinesulfonylaniline carbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =4-(2'-thiazole)sulfonylaniline carbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H,, R ₇ =OCH ₃ ; R ₃ =4-(2'-pyrimidine)sulfamoylanilide carbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H,, R ₇ =OCH ₃ ; R ₃ =4-(4',6'-dimethylpyrimidine-2')sulfamoylanilide carbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =4-(5',6'-dimethoxypyrimidine-4')sulfonylanilide carbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =4-(5'-CH ₃ -isoxazole-3')sulfonylaniline carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ ; R ₃ =p-OCH ₃ -anilinecarbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =p-sulfoanilinocarbonyl, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =p-COOH-aniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =m-COOH-aniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =o-COOH-aniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =p-OH-anilinecarbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =m-OH-p-CO ₂ H aniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =m-CO ₂ Hp-OH-aniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =4-ethoxycarbonylaniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =m-CF ₃ -anilinecarbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =m-CF ₃ -4-NO ₂ -anilinocarbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =4-sulfonylaniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =4-guanidinesulfonylaniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =4-(2'-thiazole)sulfonylaniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =4-(2-pyrimidine)sulfonylaniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =4-(4',6'-dimethylpyrimidine-2')sulfamoylanilide carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =4-(5',6'-dimethoxypyrimidine-4')sulfonylanilide carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =(5'-CH ₃ -isoxazole-3')-4-sulfonylaniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =p-OCH ₃ -anilinecarbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =p-sulfoanilinocarbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₃ =p-COOH-anilinecarbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =m-COOH-anilinecarbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =o-COOH-aniline carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ .R ₈ =CH ₃ ; R ₃ =m-OH-p-COOH-anilinecarbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =m-COOH-p-OH-aniline carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =o-COOH-pI-anilinecarbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =p-ethoxycarbonylaniline carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =m-CF ₃ -anilinecarbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =m-CF ₃ -4-NO ₂ -anilinocarbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =4-sulfonylaniline carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =4-guanidinesulfonylaniline carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =4-(2'-thiazole)sulfonylaniline carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =4-(2'-pyrimidine)sulfamoylanilide carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =4-(4',6'-dimethylpyrimidine-2')sulfamoylanilide carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =4-(5',6'-dimethoxypyrimidine-4')sulfonylanilide carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ = _CH3 ; R ₃ =(5'-CH ₃ -isoxazole-3')-4-sulfamoylanilide carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =p-OCH ₃ -anilinecarbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =p-sulfoaniline carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ R ₈ =CH ₃ ; R ₃ =p-COOH-aniline carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =R ₈ =OCH ₃ ; R ₃ =m-OH-p-COOH-anilinecarbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =R ₈ =OCH ₃ ; R ₃ =m-COOH-p-OH-aniline carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =R ₈ =OCH ₃ ; R ₃ =p-ethoxycarbonylaniline carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =R ₈ =OCH ₃ ; R ₃ =m-CF ₃ -anilinecarbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =R ₈ =OCH ₃ ; R ₃ =m-CF ₃ -p-NO ₂ -anilinocarbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =R ₈ =OCH ₃ ; R ₃ =m-carboxymethyleneoxyaniline carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =R ₈ =OCH ₃ ; R ₃ =4-sulfonylaniline carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =R ₈ =OCH ₃ ; R ₃ =4-guanidinesulfonylaniline carbonyl, R ₄ =R ₅ =R ₆ =H, R ₇ =R ₈ =OCH ₃ ; R ₃ =p-COOH-anilinecarbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =m-COOH-anilinecarbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =o-COOH-anilinecarbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =o-OH-anilinecarbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =m-OH-anilinecarbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =p-OH-anilinecarbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =m-OH-p-COOH-anilinecarbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =m-COOH-p-OH-aniline carbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =p-ethoxycarbonylaniline carbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =m-CF ₃ -anilinecarbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =m-CF ₃ -p-NO ₂ -anilinocarbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =4-sulfonylaniline carbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =4-guanidinesulfonylaniline carbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =4-(2'-thiazole)sulfonylaniline carbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =4-(2'-pyrimidine)sulfamoylanilide carbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =4-(4',6'-dimethylpyrimidine-2')sulfamoylanilide carbonyl, R ₄ =R ₅ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =4-(5',6'-dimethoxypyrimidine-4')sulfonylanilide carbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =4-(5'-CH ₃ -isoxazole-3')sulfamoylanilide carbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₃ =p-OCH ₃ -anilinecarbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ,; R ₃ =p-COOH-aniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Cl, R ₇ =OCH ₃ ; R ₃ =m-OH-p-COOH-anilinecarbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Cl, R ₇ =OCH ₃ ; R ₃ =m-COOH-p-OH-aniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Cl, R ₇ =OCH ₃ ; R ₃ =p-ethoxycarbonylaniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Cl, R ₇ =OCH ₃ ; R ₃ =m-CF ₃ -anilinecarbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Cl, R ₇ =OCH ₃ ; R ₃ =4-sulfonylaniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Cl, R ₇ =OCH ₃ ; R ₃ =4-guanidinesulfonylaniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Cl, R ₇ =OCH ₃ ; R ₃ =4-(5',6'-dimethoxypyrimidine-4')sulfonylanilide carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Cl, R ₇ =OCH ₃ ; R ₃ =p-COOH-anilinecarbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Br, R ₇ =OCH ₃ ; R ₃ =o-COOH-aniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Br, R ₇ =OCH ₃ ; R ₃ =m-OH-p-COOH-anilinecarbonyl, R ₄ =R ₅ =R ₈ =H, R = Br, R ₇ =OCH ₃ ; R ₃ =o-COOH-pI aniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Br, R ₇ =OCH ₃ ; R ₃ =p-ethoxycarbonylaniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Br, R ₇ =OCH ₃ ; R ₃ =m-CF ₃ -anilinecarbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Br, R ₇ =OCH ₃ ; R ₃ =4-aminosulfonylaniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Br, R ₇ =OCH ₃ ; R ₃ =p-OCH ₃ -anilinecarbonyl, R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ,; R ₃ =p-COOH-aniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =n-Hex, R ₇ =OCH ₃ ; R ₃ =o-COOH-phenylaminocarbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =n-Hex, R ₇ =OCH ₃ ; R ₃ =m-OH-p-COOH-aniline carbonyl, R ₄ =R ₅ =R ₈ =H, R = Hex, R ₇ =OCH ₃ ; R ₃ =o-COOH-pI-anilinecarbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =n-Hex, R ₇ =OCH ₃ ; R ₃ =p-ethoxycarbonylaniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Hex, R ₇ =OCH ₃ ; R ₃ =m-CF ₃ -anilinecarbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Hex, R ₇ =OCH ₃ ; R ₃ =4-aminosulfonylaniline carbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Hex, R ₇ =OCH ₃ ; R ₃ =p-OCH ₃ -anilinecarbonyl, R ₄ =R ₅ =R ₈ =H, R ₆ =Hex, R ₇ =OCH ₃ ; R ₃ =p-COOH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =m-COOH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =p-OCH ₃ -anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =m-OH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =o-OH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =p-ethoxycarbonylaniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =m-OH-p-COOH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =m-COOH-p-OH aniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =m-CF ₃ -anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =m-CF ₃ -p-NO ₂ -anilinocarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =4-sulfonylaniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =4-guanidinosulfonylaniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =4-(2'-pyrimidine)sulfamoylanilide carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =4-(5',6'-dimethoxypyrimidine-4')sulfonylanilide carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =4-(2'-thiazole)sulfonylaniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =p-COOH-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OH, R ₈ =NO ₂ ; R ₃ =p-OCH ₃ -anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OH, R ₈ =NO ₂ ; R ₃ =m-OH-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OH, R ₈ =NO ₂ ; R ₃ =o-OH-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OH, R ₈ =NO ₂ ; R ₃ =p-ethoxycarbonylaniline carbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OH, R ₈ =NO ₂ ; R ₃ =m-OH-p-COOH-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OH, R ₈ =NO ₂ ; R ₃ =m-COOH-p-OH-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OH, R ₈ =NO ₂ ; R ₃ =m-CF ₃ -anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OH, R ₈ =NO ₂ ; R ₃ =4-sulfamoyl-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OH, R ₈ =NO ₂ ; R ₃ =4-guanidinesulfonyl-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OH, R ₈ =NO ₂ ; R ₃ =4-(2'-thiazole)sulfamoyl-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OH, R ₈ =NO ₂ ; R ₃ =p-COOH-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ , R ₈ =NO ₂ ; R ₃ =p-OH-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ , R ₈ =NO ₂ ; R ₃ =p-OCH ₃ -anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ , R ₈ =NO ₂ ; R ₃ =p-ethoxycarbonylaniline carbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OH, R ₈ =NO ₂ ; R ₃ =4-guanidinesulfonyl-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ , R ₈ =NO ₂ ; R ₃ =p-COOH-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =o-COOH-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =p-OH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =m-OH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =o-OH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =p-OCH ₃ -anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =p-ethoxycarbonylaniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =m-OH-p-COOH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =m-COOH-p-OH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ R ₃ =m-CF ₃ -anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ R ₃ =m-CF ₃ -p-NO ₂ -anilinocarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ R ₃ =4-sulfamoyl-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =4-guanidinosulfonyl-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =4-(2'-pyrimidine)sulfamoyl-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =4-(5',6'-dimethoxypyrimidine-4')sulfonylanilide carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =4-(2'-thiazole)sulfamoyl-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =o-OH-pI-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =p-COOH-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =m-COOH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =o-COOH-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =p-OH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =m-OH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =o-OH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =p-OCH ₃ -anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =p-ethoxycarbonylaniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =m-OH, p-COOH-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =m-CF ₃ -anilinocarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =m-CF ₃ -pI-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =4-guanidinosulfonyl-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =4-sulfamoyl-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =4-(5',6'-dimethoxypyrimidine-4')sulfonylanilide carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =4-(2'-thiazole)sulfamoyl-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =4-(2'-pyrimidine)sulfamoyl-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =p-COOH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =p-OH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =m-OH-phenylcarbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =o-OH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =p-OCH ₃ -anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =ethoxycarbonylanilinecarbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =CF ₃ -anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =4-sulfonylaniline carbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =4-guanidinesulfonylaniline carbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =4-(2'-pyrimidine)sulfonylanilide carbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =4-(5',6'-dimethoxypyrimidine-4')sulfonylanilide carbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =4-(2'-thiazole)sulfonylaniline carbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =o-COOH-aniline carbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =p-OH-anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OCH ₃ ; R ₃ =ethoxycarbonylanilinocarbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OCH ₃ ; R ₃ =p-OCH ₃ -anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OCH ₃ ; R ₃ =p-OCH ₃ -anilinecarbonyl, R ₄ =R ₅ =H, R ₆ =Cl, R ₇ =OH, R ₈ =NO ₂ ; R ₃ =4-guanidinesulfonylaniline carbonyl, R ₄ =R ₅ =H, R ₆ =Cl, R ₇ =OH, R ₈ =NO ₂ ; R ₃ =m-OH-pCOOH-anilinecarbonyl, R ₄ =H, R ₅ =CH ₃ , R ₇ =OH, R ₆ =R ₈ =NO ₂ ; R ₃ =p-COOH-aniline carbonyl, R ₄ =H, R ₅ =CH ₃ , R ₇ =OH, R ₆ =R ₈ =NO ₂ ; R ₃ =m-COOH-aniline carbonyl, R ₄ =H, R ₅ =CH ₃ , R ₇ =OH, R ₆ =R ₈ =NO ₂ ; R ₃ =o-COOH-aniline carbonyl, R ₄ =H, R ₅ =CH ₃ , R ₇ =OH, R ₆ =R ₈ =NO ₂ ; R ₃ =p-OCH ₃ -anilinecarbonyl, R ₄ =H, R ₅ =CH ₃ , R ₇ =OH, R ₆ =R ₈ =NO ₂ ; R ₃ =p-ethoxycarbonylaniline carbonyl, R ₄ =H, R ₅ =CH ₃ , R ₇ =OH, R ₆ =R ₈ =NO ₂ ; R ₃ =p-sulfamoylaniline carbonyl, R ₄ =H, R ₅ =CH ₃ , R ₇ =OH, R ₆ =R ₈ =NO ₂ ; R ₃ =p-guanidinesulfonylanilide carbonyl, R ₄ =H, R ₅ =CH ₃ , R ₇ =OH, R ₆ =R ₈ =NO ₂ ; R ₃ =4-(2'-pyrimidine)sulfamoylanilide carbonyl, R ₄ =H, R ₅ =CH ₃ , R ₇ =OH, R ₆ =R ₈ =NO ₂ ; R ₃ =4-(2'-thiazole)sulfonylaniline carbonyl, R ₄ =H, R ₅ =CH ₃ , R ₇ =OH, R ₆ =R ₈ =NO ₂ ; R ₃ =4-(4',6'-dimethylpyrimidine-2')sulfonylanilide carbonyl, R ₄ =H, R ₅ =CH ₃ , R ₇ =OH. R ₃ =CONH(CH) ₃ COOH, R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ;

_R4 = _R5 = _R6 = _R8 =H, R= _OCH3 ;

R ₄ =R ₅ =R ₆ =R ₈ =H, R ₇ =OCH ₃ ; R ₃ =CONH(CH) ₃ COOH, R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ; R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ;

R ₄ =R ₅ =R ₈ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ ;

R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ;

R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ;

R ₄ =R ₆ =R ₈ =H, R ₈ =CH ₃ , R ₇ =OCH ₃ ;

R ₄ =R ₆ =R ₈ =H, R ₅ =CH ₃ , R ₇ =OCH ₃ ; R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ;

R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₄ =R ₅ =R ₆ =H, R ₇ =OCH ₃ , R ₈ =CH ₃ ;

R ₄ =R ₅ =R ₈ =H, R ₆ =Br, R ₇ =OCH ₃ ;

R ₄ =R ₅ =R ₈ =H, R ₆ =Br, R ₇ =OCH ₃ ; R ₄ =R ₅ =R ₈ =H, R ₆ =Br, R ₇ =OCH ₃ ; R ₄ =R ₅ =R ₈ =H, R ₆ =Hex, R ₇ =OCH ₃ ; R ₄ =R ₅ =R ₈ =H, R ₆ =Hex, R ₇ =OCH ₃ ;

R ₄ =R ₅ =R ₈ =H, R ₆ =Hex, R ₇ =OCH ₃ ;

R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ;

R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ;

R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =CO ₂ C ₂ H ₅ , R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =CO ₂ H, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =R ₈ =OCH ₃ ; R ₃ =CO ₂ C ₂ H ₅ , R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =CO ₂ H, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =CO ₂ C ₂ H ₅ , R ₄ =R ₅ =H, R ₆ =NH ₂ , R ₇ =OH, R ₈ =CH ₃ ; R ₃ =CO ₂ H, R ₄ =R ₅ =H, R ₆ =NO ₂ , R ₇ =OCH ₃ , R ₈ =CH ₃ ; R ₃ =CO ₂ C ₂ H ₅ , R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OH, R ₈ =NO ₂ ; R ₃ =CO ₂ H, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OH, R ₈ =NO ₂ ; R ₃ =CO ₂ C ₂ H ₅ , R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ , R ₈ =NO ₂ ; R ₃ =CO ₂ H, R ₄ =R ₅ =H, R ₆ =C ₂ H ₅ , R ₇ =OCH ₃ , R ₈ =NO ₂ ; R ₃ =CO ₂ C ₂ H ₅ , R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =CO ₂ H, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OCH ₃ ; R ₃ =CO ₂ C ₂ H ₅ , R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OCH ₃ ; R ₃ =CO ₂ H, R ₄ =R ₅ =H, R ₆ =R ₈ =NO ₂ , R ₇ =OCH ₃ ; R ₃ =CO ₂ C ₂ H ₅ , R ₄ =R ₅ =H, R ₆ =Cl, R ₇ =OH, R ₈ =NO ₂ ; R ₃ =CO ₂ H, R ₄ =R ₅ =H, R ₆ =Cl, R ₇ =OH, R ₈ =NO ₂ ; R ₃ =CO ₂ H, R ₄ =H, R ₅ =CH ₃ , R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =CO ₂ C ₂ H ₅ , R ₄ =H, R ₅ =CH ₃ , R ₆ =R ₈ =NO ₂ , R ₇ =OH; R ₃ =R ₅ =R ₆ =R ₈ =H, R ₇ =CH ₃ ; R ₃ =R ₅ =R ₆ =R ₈ =H, R ₇ =CH ₃ ;

R ₃ =R ₅ =R ₆ =R ₈ =H, R ₇ =CH ₃ ; R ₃ =R ₅ =R ₆ =R ₈ =H, R ₄ =CH ₃ ,

R ₃ =R ₅ =R ₆ =R ₈ =H, R ₄ =CH ₃ ,

R ₃ =R ₅ =R ₆ =R ₈ =H, R ₄ =CH ₃ , R ₃ =R ₅ =R ₆ =R ₈ =H, R ₄ =CH ₃ , R ₃ =R ₅ =R ₆ =R ₈ =H, R ₄ =CH ₃ ,

R ₃ =R ₅ =R ₆ =R ₈ =H, R ₄ =CH ₃ , R ₃ =R ₅ =R ₆ =R ₈ =H, R ₄ =CH ₃ , R ₃ =R ₅ =R ₆ =R ₈ =H, R ₄ =CH ₃ ,

R ₃ =R ₅ =R ₆ =R ₈ =H, R ₄ =CH ₃ , R ₃ =R ₅ =R ₆ =R ₈ =H, R ₄ =CH ₃ , R ₃ =R ₅ =R ₆ =R ₈ =H, R ₄ =CH ₃ ,

R ₃ =R ₅ =R ₆ =R ₈ =H, R ₄ =CH ₃ ,

R ₃ =R ₅ =R ₆ =R ₈ =H, R ₄ =CH ₃ , R ₃ =R ₅ =R ₆ =R ₈ =H, R ₄ =CH ₃ , R ₃ =R ₅ =R ₆ =H, R ₄ =R ₈ =CH ₃ , R ₆ =R ₅ =R ₆ =H, R ₄ =R ₈ =CH ₃ ,

R ₃ =R ₅ =R ₆ =H, R ₄ =R ₈ =CH ₃ , R ₃ =R ₄ =R ₅ =R ₇ =R ₈ =H,

R ₃ =R ₄ =R ₅ =R ₇ =R ₈ =H,

6. The compound according to claim 1, characterized in that the compound further comprises a pharmaceutically acceptable salt, a hydrate of a salt, an ester or a prodrug thereof. 7. The method for preparing the compound as claimed in claim 1, characterized in that, substituted 3-carboxy coumarin, substituted 4-carboxy coumarin, substituted 6-carboxy coumarin or substituted 7 -Condensation of carboxycoumarins with corresponding substituted amines or hydrazines. 8. The method for preparing the compound as claimed in claim 1, characterized in that, substituted 3-carboxy coumarin, substituted 4-carboxy coumarin, substituted 6-carboxy coumarin or substituted 7 After the condensation of -carboxycoumarin with the corresponding substituted hydrazine compound, the formed hydrazide undergoes a one-step annulation and formation of a heterocyclic derivative. 9. The preparation method according to any one of claims 7 and 8, characterized in that the reagents used in the amidation reaction include phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, 1,3-Dicyclohexylimine (DCC), Dipyridine Carbonate (2-DPC), 1,3-Diisopropylcarboimide (DIPC), 1-(3-Dimethylaminopropyl) -3-Ethylcarboimide (EDCI); catalysts used include tertiary amines, pyridine, 4-dimethylaminopyridine, and 4-pyrrolidinylpyridine; organic solvents used include dimethyl sulfoxide (DMSO) , toluene, dichloromethane, ethylene glycol dimethyl ether, 1,2-dichloroethane, tetrahydrofuran and N,N-dimethylformamide (DMF). 10. A pharmaceutical composition, characterized in that it contains a pharmaceutically effective dose of any compound as claimed in claims 1-6, and a pharmaceutically acceptable carrier. 11. The pharmaceutical composition according to claim 9, characterized in that the pharmaceutical composition can be tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations and various particle delivery systems. 12. Use of a compound according to any one of claims 1-6 as an inhibitor of transforming growth factor-β1 (TGF-β1). 13. Use of a compound according to any one of claims 1-6 as an inhibitor of converted angiotensin II (AII). 14. Use of a compound according to any one of claims 1-6 in the preparation of a medicament for treating kidney diseases. 15. Use of the compound according to any one of claims 1-6 in the preparation of medicaments for treating cardiovascular and cerebrovascular diseases. 16. The use of the compound according to any one of claims 1-6 in the preparation of a medicament for treating type II diabetes. 17. The application according to claim 14, characterized in that said cardiovascular and cerebrovascular diseases are hypertension, heart embolism, myocardial infarction, and cerebral apoplexy.